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Roles of NIPBL in maintenance of genome stability
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Review
Roles of NIPBL in maintenance of genome stability ⁎
Danyan Gao, Bijun Zhu, Xin Cao, Miaomiao Zhang, Xiangdong Wang
Zhongshan Hospital Institute of Clinical Science, Fudan University Medical School, Shanghai Institute of Clinical Bioinformatics Shanghai, China
A R T I C LE I N FO
A B S T R A C T
Keywords: NIPBL Cohesin Genome stability Chromatin loop
A cohesin-loading factor (NIPBL) is one of important regulatory factors in the maintenance of 3D genome organization and function, by interacting with a large number of factors, e.g. cohesion, CCCTC-binding factor (CTCF) or cohesin complex component. The present article overviews the critical and regulatory roles of NIBPL in cohesion loading on chromotin and in gene expression and transcriptional signaling. We explore molecular mechanisms by which NIPBL recruits endogenous histone deacetylase (HDAC) to induce histone deacetylation and influence multi-dimensions of genome, through which NIPBL “hop” movement in chromatin regulates gene expression and alters genome folding. NIPBL regulates the process of CTCF and cohesion into chromatin loops and topologically associated domains, binding of cohesion and H3K4mes3 through interaction among promoters and enhancers. HP1 recruits NIPBL to DNA damage site through RNF8/RNF168 ubiquitylation pathway. NIPBL contributes to regulation of genome-controlled gene expression through the influence of cohesin in chromosome structure. NIPBL interacts with cohesin and then increases transcriptional activities of REC8 promoter, leading to up-regulation of gene expression. NIPBL movement among chromosomal loops regulates gene expression through dynamic alterations of genome organization. Thus, we expect a new and deep insight to understand dynamics of chromosome and explore potential strategies of therapiesc on basis of NIPBL.
1. Introduction The cohesin and CCCTC-binding factor (CTCF) play critical roles in the maintenance of three-dimensional (3D) structures of genomes, longrange interactions of nuclear chromatin, and stability of genomes. Of key elements of chromosome architecture and genome organization, cohesin at globule boundaries contributes to dynamic alternations and stabilities of local globule structures and global chromosome territories, while heterochromatin mediates chromatin fiber compaction at centromeres and promotes prominent inter-arm interactions within centromere-proximal regions [1]. CTCF/cohesin-mediated interaction creates a constructive location to spatially organize genes with CTCF-motif orientation, where cell type-specific genes toward CTCF for the transcription [2]. Cohesin functions depend on the cohesin-loading factor (NIPBL). CTCF and NIPBL interaction has unreplaceable roles in the distribution of cohesin complex component (Rad21) chromatin immunoprecipitation-seq peaks, occupancy of global Rad21 or CTCF at NIPBL loading sites, and ATP depletion biases cohesin localization toward NIPBL loading sites [3]. About 97% stripe domains appear in NIPBL and Rad21 recruitment. Different elements of noncoding genome are involved in regulation of the NIPBL gene, e.g. NIPBL-AS1 a long non-coding RNA antisense to NIPBL.
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Intergenic regions (R1 and R2) at 130 kb and 160 kb upstream of the NIPBL promoter, are considered as optimal candidates for a NIPBL distal enhancer and highly correlated with open chromatin and histone variants/marks at enhancers and active transcription [4]. Such distal enhancer can regulate expression of NIPBL, NIPBL-AS1, or diseasespecific genes. The regulation of the NIPBL gene is of great interest, since organisms are sensitive to NIPBL levels. NIPBL plays an important role in cancer cell proliferation, migration, and infiltration in the G0/ G1 phase of cell cycle, preventing from apoptosis or autophagy and generating cell resistance to drugs [5]. NIPBL is one of key factors to regulate process of CTCF and cohesin into chromatin loops and topologically associated domains (TADs), binding of cohesin with histone H3 lysine 4 trimethylation (H3K4me3) through interaction among promoters and enhancers, and 3D organization and dynamics of the genome [3,6–9]. The NIPBL- sister chromatid cohesion factor (MAU)4 complex controls loading of physically tethered cohesin rings at NIPBL sites of chromatin, extrudes along DNA, and halts at CTCF bound to inward-oriented motifs in the convergent orientation and opposite directions [3]. The present article overviews the critical and regulatory roles of NIBPL in cohesion loading on chromotin and in gene expression and transcriptional signaling. We explore molecular mechanisms by which NIPBL recruits endogenous histone deacetylase (HDAC) to
Corresponding author. E-mail address: [email protected] (X. Wang).
https://doi.org/10.1016/j.semcdb.2018.08.005 Received 20 July 2018; Accepted 6 August 2018 1084-9521/ © 2018 Elsevier Ltd. All rights reserved.
Please cite this article as: Gao, D., Seminars in Cell and Developmental Biology (2018), https://doi.org/10.1016/j.semcdb.2018.08.005
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induce histone deacetylation and influence multi-dimensions of genome, through which NIPBL “hop” movement in chromatin regulates gene expression and alters genome folding. 2. “Porter” role of NIPBL in cohesin loading on DNA NIPBL (also named CDLS, IDN3, SCC2, CDLS1, IDN3-B) encodes the homolog of Nipped-B like protein and colon tumor susceptibility 2-type sister chromatid cohesion proteins, to facilitate enhancer-promoter interaction of remote enhancers. During mitotic process, cohesin assistes in replicating chromatids and promoting the repair of DNA damage. NIPBL is indispensable during process of loading the cohesin complex onto DNA [10] and a core part of cohesin complex associated with stromal antigen subunit SA1 or SA2. Loss of cohesin integrity results in end-joining of distant DNA double strand breaks (DSBs) which is nonhomologous [11,12]. NIPBL and MAU2 heterodimer is comprised of a separate ‘loader’ complex to facilitate the initial association of cohesin with DNA. N- and C-terminals of NIPBL are pivotal to load dohesin on DSBs. Heterochromatin protein 1 (HP1) recruits NIPBL to DNA damage sites, and has three isoforms (HP1α, β, γ), of which HP1γ appears to retain the HP1 domain fragment at DNA damage. The N-terminus of NIPBL was recruited to DSBs through the corresponding HP1-binding motif, which was assisted by HP1γ. HP1 regulates the recruitment and accumulation of NipblN, probably through a motif binding to the Nterminus of NIPBL [10]. For example, HP1 binding motif and vitamin D receptor gene nuclease are required for the recruitment of NIPBLN to DNA damage [13]. HP1-mediated recruitment is independent upon MAU2, while requests the presence of ring finger protein (RNF)168 ubiquitin ligase in DNA damage-dependent RNF8/RNF168 signaling [13]. The sensor protein MDC1 recruits RNF8 to ubiquitinated histone H1 and then to RNF168, resulting in more potent histone H2A Soymilk [14–16]. The role and recruitment of NIPBL adhesion in DNA damage sites varies among types of impaired DNA. Through HEAT repeat domains, the recruitment of NIPBL C-terminal to DSBs is triggered by laser microirradiation. Recruitment approaches for NIPBL depend on the RNF8/RNF168 ubiquitylation pathway, where MDC1 recruits RNF8 to ubiquitinated histone H1, followed by RNF168, polyubiquitinated histone H2A, downstream to 53BP1, BRCA1, and mucin-associated structural maintenance of chromosomes (SMC)5/6 complexes [17–20]. In addition, ATM/ATR serine/threonine kinase activity is required in the C-terminal mediated recruitment of NIPBL. Cohesin is enriched in the endonuclease-derived flanking regions of protein coding debris buster and highly dependent upon the NIPBL/MAU2 loading subcomplex. NIPBL and MAU2 complexes loading to DSBs is a prerequisite for repairing the DNA damage through cohesin binding to DNA during separate "load" at the end of the cell [10,21,22]. Early components γH2AX and Mre11 produced in DNA damage response are also required for the accumulation of cohesin on DSBs. NIPBL plays a highly dynamic role in maintaining genetic stability and forms a complex in response to damaged DNA (Fig. 1). The sister chromatid cohesin (SCC) is established during S phase and plays a central role in accurate segregation of chromosome and efficient repair of DSBs. The chromosomes segregation and G2-phase DSB repair can be hardly achieved with cohesin [22].
Fig. 1. Cohesin loading factor (NIPBL)-dominant transcriptional reguations. Challenges. trigger DNA damage characterized by double strand breaaks (DSBs). The C- and N-terminals of NIPBL is recruited to DSBs, through HEAT repeat domain and the corresponding heterochromatin protein 1 (HP1)-binding motif, respectively, in assistance with HP1γ. The recruitment approaches for NIPBL depend on the ring finger protein (RNF)8/RNF168 ubiquitylation pathway. ATM/ATR activity is required in the C-terminal mediated recruitment of NIPBL in addition to RNF8/RNF168 ubiquitylation pathway.
physiological transit of NIPBL fused with MAU2 to the nucleus is a critical step of cell proliferation [5]. MAU2 as an chromatin linker targets NIPBL to specific chromosomal protein acceptor sites and acts as an independent role if NIPBL exists at the location of DNA damage [10]. MAC2 roles in recruitment of NIPBL can be replaced with distinct protein domains through different mechanisms of NIPBL recruitment. NIPBL isoforms accumulate on the debris buster and NIPBL and MAU2 heterodimer are recruited to damaged DNA, to play roles of adhesin loading in chromosome segregation during DNA repair [25,26]. Cohesin plays an important role in the formation of the chromosome structure that influences the gene expression. S-phase mucins and DSBinduced mucins play important roles in the process of SCC. Cohesin binding to chromosome promotes chromosome segregation and DNA repair, while adhesin proteins assist in the establishment of chromosomal boundaries, bind to mating loci, and limit the spread of gene silencing messages [27]. NIPBL is necessary for the aggregation of sister chromatids during meiosis, where meiotic recombination protein (REC8) encodes a specific adhesin subunit. At meiotic stage, REC8 activation, mucins, and annexin recruitment to the sister chromatid require the existence of NIPBL to promote the cohesin loading onto chromosome [28] and maintain levels of REC8 in meiotic cells. NIPBL enhances transcriptional activity of REC8 promoter through NIPBL and cohesin interaction during meiosis after REC8 mRNA production. REC8 was minimally mapped on meiotic chromosomes in depletion of NIPBL. Of 792 binding sites identified for NIPBL, majority sites are located on the meiotic chromosome for meiosis accompanied by sister chromosome [26]. NIPBL and MAU2 complex contributes to recruitment of adhesins to sister chromatid in chromosome, since cohesin regulates the proper concentration of chromosomes and promotes the formation of the chromosomal loops [29,30]. NIPBL and MAU2 complex promotes the extension of chromatin loops to form TADs as autonomous transcriptional units. Of the complex, MAC2 regulates the interaction with NIPBL and contact frequency between loop anchors. Cohesin release factor WAPL has the decisive role in control of MAC2 expression, MAC2-regulated length of extended loops [31]. WAPL restricts the loop formation between incorrect CTCF sites and is involved in the release of chromosomal loop through the open of a distinct DNA exit gate, when
3. Regulatory roles of NIPBL in gene expression Cohesin regulates gene expression and controls cell cycle, which is influenced with gene variants, SMC1A, SMC3, and HDAC 8 in cohesin complex [23]. The process of NIPBL variant recruitment to DNA damage is important for maintenance of 3D genome organization and initiation of repair and is associated with isoforms of NIPBL. NIPBL has A and B isoform at 316 and 304 kDa proteins, respectively. Responses of cells with different isoforms of NIPBL to DNA damage vary [24]. The 2
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differentiation stage-specific manner. Interactions are regulated by post-translational modifications or availability of interacting proteins, to recruit cohesin to multiple sites varied among cell types and provide further versatility fot actions. 4. NIPBL recruits endogenous HDAC to induce histone deacetylation Acetylated histones in mitosis induce chromosome structural defects and abnormal chromosome numbers such as aneuploidy [39]. When histones are highly acetylated during mitotic condensation, mitotic chromosomes with 3D structure are produced and chromatin remodeling is altered [40]. NIPBL can initiate deacetylation of lysine 9 of histone 3 (H3K9) for methylation and recruits HDACs to mediate local chromatin modifications [41]. It has been revealed that histone modifications affect cohesin recruitment to specific chromosomal loci. Acetylation of histone protein facilitates the dissociation of DNA, histone octamer, and relaxation of nucleosome structure. Various transcription factors and co-transcription factors specifically bind to DNA binding sites and activate gene transcription. NIPBL-binding proteins isolate chromatin-modifying cofactors by deacetylating histones or HDAC1 and HDAC3. NIPBL fused to the GAL4-DNA binding domain inhibits the promoter activity of numerous genes by recruitment of HDACs, which was reduced by the missense mutation of NIPBL in disease, due to HDAC inhibition [34]. 5. NIPBL “hops” among chromosomal loops NIPBL movement in chromatin regulates gene expression through alterations of chromosome organization. NIPBL is a hook protein with the N-terminal domain to bind with MAU2 and form cohesin-loaded complex [42]. NIPBL plays an essential role in cohesin loading onto chromosomes, rather than sister chromatids [43,44]. Cohesin complex mediates the process of DNA-DNA interactions between SCC and DNA loop. NIPBL-regulated cohesin loading onto chromosomes is initiated by stimulating cohesin ABC-like ATPase and post-loading function in driving loop extrusion. NIPBL binds dynamically to chromatin and moves within chromatin consistent with a’ stop-and-go’ or’ hopping’ motion [45,46] (Fig. 3). NIPBL, Pds5 and SCC3 (SA1/2) among HEAT repeat containing proteins associated with kleisins regulated the process of cohesin interactions with chromatin. For example, NIPBL regulates the initial interaction of cohesin with DNA with the assistance of ATP hydrolysis after stimulating cohesin ATPase [45,47–49]. NIPBL plays a role in TADs formation and cohesin loops loaded on chromosomes. As a hook protein about 316 kDa with the N-terminal domain, NIPBL binds to MAU2 and adhesins, forms adhesin-loaded complex for cohesin loading onto chromosomes, and acts as a potent activator of ATP hydrolysis by adhesins [50]. NIPBL binds NIPBL stimulates ATPases of adhesins, contributes to TADs formation, and transiently interact with chromosomes before and after DNA replication [51]. NIPBL is dissociated from chromatin in the early stages and eliminated from the chromosome during mitosis. NIPBL binds to chromatin more rapidly and frequently than dolastin with a residence time of 15–30 m [45]. The separation of NIPBL molecules from chromatin quickly reappears throughout the bleaching zone. The NIPBL diffused through or across the nucleus is severely slow, leading to the low mobility phenomenon [45]. Chemokines play an essential role in the binding of NIPBL to chromosomes. The increased rate of SCC1 degradation restored may slow down the diffusion of NIPBL in nucleu by interaction between NIPBL and soluble adhesin pools and jumping between adjacent chromosomal protein complexes [45]. One of outstanding studies performed by Rhodes et al desbribes NIPBL interactions and colocalizations with cohesin outside of the loading reaction using live cell imaging [45]. It seems that cohesion modulates the density of NIPBL dynamically rapidly during NIPBL
Fig. 2. Roles of NIPBL-cohesin interactions in genome stability. A: The cohesin complex loop together with CCCTC-binding factor (CTCF) sites forms into 3D genome, including processive enlargement of loops and polyclonal collections of loops shaping topologically associated domains (TADs). Nipbl stimulates cohesin ATPase and facilitate the formation of TADs [45]. B: The horizontal axis is the promoting role of NIPBL and sister chromatid cohesion factor (MAU)2 complex in loop extension, and the vertical axisrepresents the inhibiting role of cohesin release factor (WAPL), of which the balance plays important role in chromation stability. C: The difference of chromatin loop lengh exists in presence or absence of WAPL, which restricts the loop extension. D: Open of a distinct DNA exit gate at the interface interacts with cohesin mucin-associated structural maintenance of chromosomes (SMC)3 and sister chromatid cohesin (SCC)1 subunits. WAPL promotes cohesin release from chromatin.
ATPase conformation is changed at the interface with SMC3 and SCC1 (Fig. 2). WAPL contributes to regulation of loop length by increasing turnover of cohesin on chromation and decreasing contact frequency between cohesion, DNA and nearby TADs [32–34]. TADs are constituted of the cohesin complex loop with processive enlargement and polyclonal collections of CTCF site. The size of chromosomal loop is up-regulated with NIPBL/MAU2 complex and downregulated with WAPL. Stability of the loop is maintained by balance between NIPBL/MAU2 complex and WAPL (Fig. 2C) and cohesin colocalization with CTCF [31,35]. Adhesins are located on the chromosomal CTCF binding site, where cohesin acts as an insulator to block interaction between enhancer and corresponding promoter [36–38]. Increased binding of cohesin with NIPBL or MAU2 can trigger cohesin accumulation at specific genomic regions. Potential interaction surfaces on cohesin, NIPBL, and MAU2, may be targeted by interactions with sequence-specific transcription factors, chromatin remodelers, specific histone mark readers, and even with RNA. Of those interactions, many occur at a specific subcellular and/or genomic location in cell cycle or 3
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RNF168 ubiquitylation pathway. NIPBL plays an important role in cohesin loading on DNA and a highly dynamic role in maintaining genetic stability and forming the complex in response to damaged DNA. NIPBL contributes to regulation of genome-controlled gene expression through the influence of cohesin in chromosome structure. NIPBL interacts with cohesin and then increases transcriptional activities of REC8 promoter, leading to up-regulation of gene expression. NIPBL recruits endogenous HDAC to induce histone deacetylation during mitotic condensation and mediate modifications of local chromatins. NIPBL movement among chromosomal loops regulates gene expression through dynamic alterations of genome organization. NIPBL interacts with cohesin as a key chromatin organizer of genome functions in mitosis and interphase and is one of the most sensitive factors contributing to developmental processes [57]. NIPBL dysfunction has been suggested to be associated abnormality of chromosome condensation, reducing cohesin loading at the β-globin locus in embryonic liver and long-distance chromatin interactions [58]. It is questioned if NIPBL can be a biology- or disease-specific biomarker candidate measurable, repeatable, and targetable. It is questioned about the specificity of NIPBL in represidentive to cohesin function, CTCF binding, transcriptional regulation, disease severity, duration, and sensitivity to therapies [59–65]. In addition to the loading of cohesin or other SMC complexes [66], NIPBL with WAP1 control cohesin colocalization on the longitudinal axis of metaphase chromosomes depending upon ATPase activity. Specificity and regulatory function of NIPBL should be furthermore investigated in single cell level using technology of clustered regularly interspaced short palindromic repeats, to define roles of NIPBL in genome folding, gene expression, heterogeneity, phenomes, and sensitivity to therapy [67–72]. Thus, we expect a new and deep insight to understand dynamics of chromosome and explore potential strategies of therapiesc on basis of NIPBL.
Fig. 3. NIPBL movement within chromatin is a’ stop-and-go’ from a to b in the line A or’ hopping’ motion from b to c between lines A and B. NIPBL hops between cohesins loaded on DNA and ensures cohesin interactions with chromatin in binding modes. NIPBL is located in nuclur during interphase, dissociated from chromatin in prophase, and excluded from chromosomes during mitosis. Nipbl, pds5,scc3 regulate cohesin's association with chromatin and the first step of association between them is regulated by nipbl and also involve ATP hydrolysis [50,73]. Beyond CTCF binding sites, CTCF may prevent cohesin’s association with Nipbl, stop ATP hydrolysis by cohesin and halt extrusion of loops in line C [45].
movement between chromosomal cohesin complexes with special vicinity. NIPBL performs different functions from loading in a low stoichiometry relative to cohesin and a high affinity for chromosomal cohesion. Using timelapse confocal microscopy confirmed, NIPBL was found to be located in nucleu during interphase, dissociated from chromatin in prophase, and excluded from chromosomes during mitosis [52–54].
Acknowledgements The work was supportedby Zhongshan Distinguished Professor Grant (XDW), The National Nature Science Foundation of China (91230204, 81270099, 81320108001, 81270131, 81300010, 81700008), The Shanghai Committee of Science and Technology (12JC1402200, 12431900207, 11410708600, 14431905100), Operation funding of Shanghai Institute of Clinical Bioinformatics, Ministry of Education for Academic Special Science and Research Foundation for PhD Education (20130071110043), and National Key Research and Development Program (2016YFC0902400, 2017YFSF090207).
6. Roles of NIPBL in genome folding Compartment subtypes to megakaryocytoplasmic (TAD) and megabase-large active and inactive compartments play important roles in maintaining chromosome organization and genome folding [54], although it is still unclear how those are formed, interacted, and affectedin genome organization. NIPBL deletion in mouse liver resulted in a significant recombination of chromosome folding [55]. Key features of 3D structure in metazoans include TADs, compartmentalization, and peak interactions [56]. Cohesin plays decisive roles in loading of chromatin by adhesin-NIPBL/NIPBL in interphase chromatin, evidenced in loss of Nipb1 in non- dividing hepatocytes withour NIPBL by using a liver-specific tamoxifen-induced Cre driver [10]. Reduction of chromatin-induced adhesin induces transfer of laminin from chromatin fraction to soluble nuclear fraction indicates NIPBL/MAU2 complex promotes the formation of chromatin loop extensions and TADs [31,48] and balance between NIPBL/MAU2 and WAPL activities regulates cohesin contributions to correct structural formation of chromosomes. NIPBL/MAU2 complexes through which cohesin is loaded onto DNA, which is released by the LBD driven by the adhesion protein antagonist [42].
References [1] T. Mizuguchi, G. Fudenberg, S. Mehta, J.M. Belton, N. Taneja, H.D. Folco, P. FitzGerald, J. Dekker, L. Mirny, J. Barrowman, S.I.S. Grewal, Cohesin-dependent globules and heterochromatin shape 3D genome architecture in S. pombe, Nature 516 (2014) 432–435. [2] Z. Tang, O.J. Luo, X. Li, M. Zheng, J.J. Zhu, P. Szalaj, P. Trzaskoma, A. Magalska, J. Wlodarczyk, B. Ruszczycki, P. Michalski, E. Piecuch, P. Wang, D. Wang, S.Z. Tian, M. Penrad-Mobayed, L.M. Sachs, X. Ruan, C.L. Wei, E.T. Liu, G.M. Wilczynski, D. Plewczynski, G. Li, Y. Ruan, CTCF-mediated human 3D genome architecture reveals chromatin topology for transcription, Cell 163 (2015) 1611–1627. [3] L. Vian, A. Pekowska, S.S.P. Rao, K.R. Kieffer-Kwon, S. Jung, L. Baranello, S.C. Huang, L. El Khattabi, M. Dose, N. Pruett, A.L. Sanborn, A. Canela, Y. Maman, A. Oksanen, W. Resch, X. Li, B. Lee, A.L. Kovalchuk, Z. Tang, S. Nelson, M. Di Pierro, R.R. Cheng, I. Machol, B.G. St Hilaire, N.C. Durand, M.S. Shamim, E.K. Stamenova, J.N. Onuchic, Y. Ruan, A. Nussenzweig, D. Levens, E.L. Aiden, R. Casellas, The Energetics and Physiological Impact of Cohesin Extrusion, Cell 173 (2018) 1165–1178 e20. [4] J. Zuin, V. Casa, J. Pozojevic, P. Kolovos, M. van den Hout, W.F.J. van Ijcken, I. Parenti, D. Braunholz, Y. Baron, E. Watrin, F.J. Kaiser, K.S. Wendt, Regulation of the cohesin-loading factor NIPBL: Role of the lncRNA NIPBL-AS1 and identification of a distal enhancer element, PLoS Genet. 13 (2017) e1007137. [5] H. Zhou, L. Zheng, K. Lu, Y. Gao, L. Guo, W. Xu, X. Wang, Downregulation of Cohesin Loading Factor Nipped-B-Like Protein (NIPBL) Induces Cell Cycle Arrest, Apoptosis, and Autophagy of Breast Cancer Cell Lines, Med. Sci. Monit. 23 (2017)
7. Conclusions and perspectives NIPBL is one of important regulatory factors in the maintenance of 3D genome organization and function, by interacting with a large number of factors, e.g. cohesion, CTCF or Rad21. NIPBL regulates the process of CTCF and cohesion into chromatin loops and TADs, binding of cohesion and H3K4mes3 through interaction among promoters and enhancers. HP1 recruits NIPBL to DNA damage site through RNF8/ 4
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[33] O. Crawley, C. Barroso, S. Testori, N. Ferrandiz, N. Silva, M. Castellano-Pozo, A.L. Jaso-Tamame, E. Martinez-Perez, Cohesin-interacting protein WAPL-1 regulates meiotic chromosome structure and cohesion by antagonizing specific cohesin complexes, Elife 5 (2016) e10851. [34] P. Jahnke, W. Xu, M. Wulling, M. Albrecht, H. Gabriel, G. Gillessen-Kaesbach, F.J. Kaiser, The Cohesin loading factor NIPBL recruits histone deacetylases to mediate local chromatin modifications, Nucleic Acids Res. 36 (2008) 6450–6458. [35] B.A. Bouwman, W. de Laat, Getting the genome in shape: the formation of loops, domains and compartments, Genome Biol. 16 (2015) 154. [36] S.J. Holwerda, W. de Laat, CTCF: the protein, the binding partners, the binding sites and their chromatin loops, Philos. Trans. R. Soc. Lond. B Biol. Sci. 368 (2013) 20120369. [37] M. Vietri Rudan, C. Barrington, S. Henderson, C. Ernst, D.T. Odom, A. Tanay, S. Hadjur, Comparative Hi-C reveals that CTCF underlies evolution of chromosomal domain architecture, Cell Rep. 10 (2015) 1297–1309. [38] A. Mora, G.K. Sandve, O.S. Gabrielsen, R. Eskeland, In the loop: promoter-enhancer interactions and bioinformatics, Brief Bioinf. 17 (2016) 980–995. [39] F. Yang, C. Baumann, M.M. Viveiros, R. De La Fuente, Histone hyperacetylation during meiosis interferes with large-scale chromatin remodeling, axial chromatid condensation and sister chromatid separation in the mammalian oocyte, Int. J. Dev. Biol. 56 (2012) 889–899. [40] E. Toselli-Mollereau, X. Robellet, L. Fauque, S. Lemaire, C. Schiklenk, C. Klein, C. Hocquet, P. Legros, L. N’Guyen, L. Mouillard, E. Chautard, D. Auboeuf, C.H. Haering, P. Bernard, Nucleosome eviction in mitosis assists condensin loading and chromosome condensation, EMBO J. 35 (2016) 1565–1581. [41] C. Pattaroni, C. Jacob, Histone methylation in the nervous system: functions and dysfunctions, Mol. Neurobiol. 47 (2013) 740–756. [42] T. Visnes, F. Giordano, A. Kuznetsova, J.A. Suja, A.D. Lander, A.L. Calof, L. Strom, Localisation of the SMC loading complex Nipbl/Mau2 during mammalian meiotic prophase I, Chromosoma 123 (2014) 239–252. [43] S. Remeseiro, A. Cuadrado, S. Kawauchi, A.L. Calof, A.D. Lander, A. Losada, Reduction of Nipbl impairs cohesin loading locally and affects transcription but not cohesion-dependent functions in a mouse model of Cornelia de Lange Syndrome, Biochim. Biophys. Acta 1832 (2013) 2097–2102 10.1098 /rsob.150178. [44] M. Ocampo-Hafalla, S. Munoz, C.P. Samora, F. Uhlmann, Evidence for cohesin sliding along budding yeast chromosomes, Open Biol. (2016) 6. [45] J. Rhodes, D. Mazza, K. Nasmyth, S. Uphoff, Scc2/Nipbl hops between chromosomal cohesin rings after loading, Elife 6 (2017). [46] C. Barrington, R. Finn, S. Hadjur, Cohesin biology meets the loop extrusion model, Chromosome Res. 25 (2017) 51–60. [47] S. Villa-Hernandez, R. Bermejo, Cohesin dynamic association to chromatin and interfacing with replication forks in genome integrity maintenance, Curr. Genet. (2018). [48] A. Lau, H. Blitzblau, S.P. Bell, Cell-cycle control of the establishment of mating-type silencing in S. Cerevisiae, Genes Dev. 16 (2002) 2935–2945. [49] Y. Murayama, F. Uhlmann, Biochemical reconstitution of topological DNA binding by the cohesin ring, Nature 505 (2014) 367–371. [50] P. Arumugam, S. Gruber, K. Tanaka, C.H. Haering, K. Mechtler, K. Nasmyth, ATP hydrolysis is required for cohesin’s association with chromosomes, Curr. Biol. 13 (2003) 1941–1953. [51] E.P. Nora, B.R. Lajoie, E.G. Schulz, L. Giorgetti, I. Okamoto, N. Servant, T. Piolot, N.L. van Berkum, J. Meisig, J. Sedat, J. Gribnau, E. Barillot, N. Bluthgen, J. Dekker, E. Heard, Spatial partitioning of the regulatory landscape of the X-inactivation centre, Nature 485 (2012) 381–385. [52] A. Pistocchi, G. Fazio, A. Cereda, L. Ferrari, L.R. Bettini, G. Messina, F. Cotelli, A. Biondi, A. Selicorni, V. Massa, Cornelia de Lange Syndrome: NIPBL haploinsufficiency downregulates canonical Wnt pathway in zebrafish embryos and patients fibroblasts, Cell Death Dis. 4 (2013) e866. [53] C.L. Tiang, Y. He, W.P. Pawlowski, Chromosome organization and dynamics during interphase, mitosis, and meiosis in plants, Plant Physiol. 158 (2012) 26–34. [54] W. Schwarzer, N. Abdennur, A. Goloborodko, A. Pekowska, G. Fudenberg, Y. LoeMie, N.A. Fonseca, W. Huber, C. HH, L. Mirny, F. Spitz, Two independent modes of chromatin organization revealed by cohesin removal, Nature 551 (2017) 51–56. [55] V. Parelho, S. Hadjur, M. Spivakov, M. Leleu, S. Sauer, H.C. Gregson, A. Jarmuz, C. Canzonetta, Z. Webster, T. Nesterova, B.S. Cobb, K. Yokomori, N. Dillon, L. Aragon, A.G. Fisher, M. Merkenschlager, Cohesins functionally associate with CTCF on mammalian chromosome arms, Cell 132 (2008) 422–433. [56] G. Fudenberg, N. Abdennur, M. Imakaev, A. Goloborodko, L.A. Mirny, Emerging evidence of chromosome folding by loop extrusion, Cold Spring Harb. Symp. Quant. Biol. 82 (2017) 45–55. [57] K. Kuleszewicz, X. Fu, N.R. Kudo, Cohesin loading factor Nipbl localizes to chromosome axes during mammalian meiotic prophase, Cell Div. 8 (2013) 12. [58] A.R. Ball Jr., Y.Y. Chen, K. Yokomori, Mechanisms of cohesin-mediated gene regulation and lessons learned from cohesinopathies, Biochim. Biophys. Acta 1839 (2014) 191–202. [59] L. Shi, M.Xu B Zhu, X. Wang, Selection of AECOPD-specific immunomodulatory biomarkers by integrating genomics and proteomics with clinical informatics, Cell Biol. Toxicol. 34 (2018) 109–123. [60] Y. Kawamura, J. Takouda, K. Yoshimoto, K. Nakashima, New aspects of glioblastoma multiforme revealed by similarities between neural and glioblastoma stem cells, Cell Biol. Toxicol. (2018), https://doi.org/10.1007/s10565-017-9420-y. [61] D. Long, T. Yu, X. Chen, Y. Liao, X. Lin, RNAi targeting STMN alleviates the resistance to taxol and collectively contributes to down regulate the malignancy of NSCLC cells in vitro and in vivo, Cell Biol. Toxicol. 34 (2018) 7–21. [62] D. Wu, X. Wang, H. Sun, The role of mitochondria in cellular toxicity as a potential drug target, Cell Biol. Toxicol. 34 (2018) 87–91.
4817–4825. [6] P. Szalaj, D. Plewczynski, Three-dimensional organization and dynamics of the genome, Cell Biol. Toxicol. (2018), https://doi.org/10.1007/s10565-018-9428-y. [7] R. Li, Y. Liu, Y. Hou, J. Gan, P. Wu, C. Li, 3D genome and its disorganization in diseases, Cell Biol. Toxicol. (2018), https://doi.org/10.1007/s10565-018-9430-4. [8] T. Ma, L. Chen, M. Shi, J. Niu, X. Zhang, X. Yang, K. Zhanghao, M. Wang, P. Xi, D. Jin, M. Zhang, J. Gao, Developing novel methods to image and visualize 3D genomes, Cell Biol. Toxicol. (2018). [9] T. Terabayashi, K. Hanada, Genome instability syndromes caused by impaired DNA repair and aberrant DNA damage responses, Cell Biol. Toxicol. (2018). [10] C. Bot, A. Pfeiffer, F. Giordano, D.E. Manjeera, N.P. Dantuma, L. Strom, Independent mechanisms recruit the cohesin loader protein NIPBL to sites of DNA damage, J. Cell. Sci. 130 (2017) 1134–1146. [11] A. Kojic, A. Cuadrado, M. De Koninck, D. Gimenez-Llorente, M. Rodriguez-Corsino, G. Gomez-Lopez, F. Le Dily, M.A. Marti-Renom, A. Losada, Distinct roles of cohesinSA1 and cohesin-SA2 in 3D chromosome organization, Nat. Struct. Mol. Biol. 25 (2018) 496–504. [12] R. Ciosk, M. Shirayama, A. Shevchenko, T. Tanaka, A. Toth, A. Shevchenko, K. Nasmyth, Cohesin’s binding to chromosomes depends on a separate complex consisting of Scc2 and Scc4 proteins, Mol. Cell 5 (2000) 243–254. [13] Y. Oka, K. Suzuki, M. Yamauchi, N. Mitsutake, S. Yamashita, Recruitment of the cohesin loading factor NIPBL to DNA double-strand breaks depends on MDC1, RNF168 and HP1gamma in human cells, Biochem. Biophys. Res. Commun. 411 (2011) 762–767. [14] T. Thorslund, A. Ripplinger, S. Hoffmann, T. Wild, M. Uckelmann, B. Villumsen, T. Narita, T.K. Sixma, C. Choudhary, S. Bekker-Jensen, N. Mailand, Histone H1 couples initiation and amplification of ubiquitin signalling after DNA damage, Nature 527 (2015) 389–393. [15] C. Doil, N. Mailand, S. Bekker-Jensen, P. Menard, D.H. Larsen, R. Pepperkok, J. Ellenberg, S. Panier, D. Durocher, J. Bartek, J. Lukas, C. Lukas, RNF168 binds and amplifies ubiquitin conjugates on damaged chromosomes to allow accumulation of repair proteins, Cell 136 (2009) 435–446. [16] G.S. Stewart, S. Panier, K. Townsend, A.K. Al-Hakim, N.K. Kolas, E.S. Miller, S. Nakada, J. Ylanko, S. Olivarius, M. Mendez, C. Oldreive, J. Wildenhain, A. Tagliaferro, L. Pelletier, N. Taubenheim, A. Durandy, P.J. Byrd, T. Stankovic, A.M. Taylor, D. Durocher, The RIDDLE syndrome protein mediates a ubiquitindependent signaling cascade at sites of DNA damage, Cell 136 (2009) 420–434. [17] M.S. Huen, R. Grant, I. Manke, K. Minn, X. Yu, M.B. Yaffe, J. Chen, RNF8 transduces the DNA-damage signal via histone ubiquitylation and checkpoint protein assembly, Cell 131 (2007) 901–914. [18] N. Mailand, S. Bekker-Jensen, H. Faustrup, F. Melander, J. Bartek, C. Lukas, J. Lukas, RNF8 ubiquitylates histones at DNA double-strand breaks and promotes assembly of repair proteins, Cell 131 (2007) 887–900. [19] N.K. Kolas, J.R. Chapman, S. Nakada, J. Ylanko, R. Chahwan, F.D. Sweeney, S. Panier, M. Mendez, J. Wildenhain, T.M. Thomson, L. Pelletier, S.P. Jackson, D. Durocher, Orchestration of the DNA-damage response by the RNF8 ubiquitin ligase, Science 318 (2007) 1637–1640. [20] M. Raschle, G. Smeenk, R.K. Hansen, T. Temu, Y. Oka, M.Y. Hein, N. Nagaraj, D.T. Long, J.C. Walter, K. Hofmann, Z. Storchova, J. Cox, S. Bekker-Jensen, N. Mailand, M. Mann, DNA repair. Proteomics reveals dynamic assembly of repair complexes during bypass of DNA cross-links, Science 348 (2015) 1253671. [21] L. Strom, H.B. Lindroos, K. Shirahige, C. Sjogren, Postreplicative recruitment of cohesin to double-strand breaks is required for DNA repair, Mol. Cell 16 (2004) 1003–1015. [22] E. Watrin, J.M. Peters, Cohesin and DNA damage repair, Exp. Cell Res. 312 (2006) 2687–2693. [23] J. Pozojevic, I. Parenti, L. Graul-Neumann, S. Ruiz Gil, E. Watrin, K.S. Wendt, R. Werner, T.M. Strom, G. Gillessen-Kaesbach, F.J. Kaiser, Novel mosaic variants in two patients with Cornelia de Lange syndrome, Eur. J. Med. Genet. (2017), https:// doi.org/10.1016/j.ejmg.2017.11.004. [24] C. Lukas, F. Melander, M. Stucki, J. Falck, S. Bekker-Jensen, M. Goldberg, Y. Lerenthal, S.P. Jackson, J. Bartek, J. Lukas, Mdc1 couples DNA double-strand break recognition by Nbs1 with its H2AX-dependent chromatin retention, EMBO J. 23 (2004) 2674–2683. [25] I. Litwin, R. Wysocki, New insights into cohesin loading, Curr. Genet. 64 (2018) 53–61. [26] J.M. Peters, T. Nishiyama, Sister chromatid cohesion, Cold Spring Harb. Perspect. Biol. 4 (2012). [27] B.D. Eads, D. Tsuchiya, J. Andrews, M. Lynch, M.E. Zolan, The spread of a transposon insertion in Rec8 is associated with obligate asexuality in Daphnia, Proc. Natl Acad. Sci. U. S. A. 109 (2012) 858–863. [28] S. Burkhardt, M. Borsos, A. Szydlowska, J. Godwin, S.A. Williams, P.E. Cohen, T. Hirota, M. Saitou, K. Tachibana-Konwalski, Chromosome cohesion established by Rec8-Cohesin in fetal oocytes is maintained without detectable turnover in oocytes arrested for months in mice, Curr. Biol. 26 (2016) 678–685. [29] J. Dekker, E. Heard, Structural and functional diversity of topologically associating domains, FEBS Lett. 589 (2015) 2877–2884. [30] J. Gassler, H.B. Brandao, M. Imakaev, I.M. Flyamer, S. Ladstatter, W.A. Bickmore, J.M. Peters, L.A. Mirny, K. Tachibana, A mechanism of cohesin-dependent loop extrusion organizes zygotic genome architecture, EMBO J. 36 (2017) 3600–3618. [31] J.H.I. Haarhuis, R.H. van der Weide, V.A. Blomen, J.O. Yanez-Cuna, M. Amendola, M.S. van Ruiten, P.H.L. Krijger, H. Teunissen, R.H. Medema, B. van Steensel, T.R. Brummelkamp, E. de Wit, B.D. Rowland, The cohesin release factor wapl restricts chromatin loop extension, Cell 169 (2017) 693–707 e14. [32] A.L. Marston, Chromosome segregation in budding yeast: sister chromatid cohesion and related mechanisms, Genetics 196 (2014) 31–63.
5
Seminars in Cell and Developmental Biology xxx (xxxx) xxx–xxx
D. Gao et al.
[69] H. Devine, R. Patani, The translational potential of human induced pluripotent stem cells for clinical neurology : The translational potential of hiPSCs in neurology, Cell Biol. Toxicol. 33 (2017) 129–144. [70] W. Wang, B. Zhu, X. Wang, Dynamic phenotypes: illustrating a single-cell odyssey, Cell Biol. Toxicol. 33 (2017) 423–427. [71] M.P. Chu, J. Kriangkum, C.P. Venner, I. Sandhu, J. Hewitt, A.R. Belch, L.M. Pilarski, Addressing heterogeneity of individual blood cancers: the need for single cell analysis, Cell Biol. Toxicol. 33 (2017) 83–97. [72] D.C. Wang, W. Wang, B. Zhu, X. Wang, Lung cancer heterogeneity and new strategies for drug therapy, Annu. Rev. Pharmacol. Toxicol. 58 (2018) 531–546. [73] J.N. Wells, T.G. Gligoris, K.A. Nasmyth, J.A. Marsh, Evolution of condensin and cohesin complexes driven by replacement of Kite by Hawk proteins, Curr. Biol. 27 (2017) R17–R18.
[63] X. Liu, J. Wu, History, applications, and challenges of immune repertoire research, Cell Biol. Toxicol. (2018), https://doi.org/10.1007/s10565-018-9426-0. [64] L. Shi, N. Dong, D. Ji, X. Huang, Z. Ying, X. Wang, C. Chen, Lipopolysaccharideinduced CCN1 production enhances interleukin-6 secretion in bronchial epithelial cells, Cell Biol. Toxicol. 34 (2018) 39–49. [65] M. Xu, X. Wang, Critical roles of mucin-1 in sensitivity of lung cancer cells to tumor necrosis factor-alpha and dexamethasone, Cell Biol. Toxicol. 33 (2017) 361–371. [66] T. Gligoris, J. Lowe, Structural Insights into Ring Formation of Cohesin and Related Smc Complexes, Trends Cell Biol. 26 (2016) 680–693. [67] W. Wang, X. Wang, Single-cell CRISPR screening in drug resistance, Cell Biol. Toxicol. 33 (2017) 207–210. [68] T. Sakuma, T. Yamamoto, Magic wands of CRISPR-lots of choices for gene knock-in, Cell Biol. Toxicol. 33 (2017) 501–505.
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Review
Roles of NIPBL in maintenance of genome stability ⁎
Danyan Gao, Bijun Zhu, Xin Cao, Miaomiao Zhang, Xiangdong Wang
Zhongshan Hospital Institute of Clinical Science, Fudan University Medical School, Shanghai Institute of Clinical Bioinformatics Shanghai, China
A R T I C LE I N FO
A B S T R A C T
Keywords: NIPBL Cohesin Genome stability Chromatin loop
A cohesin-loading factor (NIPBL) is one of important regulatory factors in the maintenance of 3D genome organization and function, by interacting with a large number of factors, e.g. cohesion, CCCTC-binding factor (CTCF) or cohesin complex component. The present article overviews the critical and regulatory roles of NIBPL in cohesion loading on chromotin and in gene expression and transcriptional signaling. We explore molecular mechanisms by which NIPBL recruits endogenous histone deacetylase (HDAC) to induce histone deacetylation and influence multi-dimensions of genome, through which NIPBL “hop” movement in chromatin regulates gene expression and alters genome folding. NIPBL regulates the process of CTCF and cohesion into chromatin loops and topologically associated domains, binding of cohesion and H3K4mes3 through interaction among promoters and enhancers. HP1 recruits NIPBL to DNA damage site through RNF8/RNF168 ubiquitylation pathway. NIPBL contributes to regulation of genome-controlled gene expression through the influence of cohesin in chromosome structure. NIPBL interacts with cohesin and then increases transcriptional activities of REC8 promoter, leading to up-regulation of gene expression. NIPBL movement among chromosomal loops regulates gene expression through dynamic alterations of genome organization. Thus, we expect a new and deep insight to understand dynamics of chromosome and explore potential strategies of therapiesc on basis of NIPBL.
1. Introduction The cohesin and CCCTC-binding factor (CTCF) play critical roles in the maintenance of three-dimensional (3D) structures of genomes, longrange interactions of nuclear chromatin, and stability of genomes. Of key elements of chromosome architecture and genome organization, cohesin at globule boundaries contributes to dynamic alternations and stabilities of local globule structures and global chromosome territories, while heterochromatin mediates chromatin fiber compaction at centromeres and promotes prominent inter-arm interactions within centromere-proximal regions [1]. CTCF/cohesin-mediated interaction creates a constructive location to spatially organize genes with CTCF-motif orientation, where cell type-specific genes toward CTCF for the transcription [2]. Cohesin functions depend on the cohesin-loading factor (NIPBL). CTCF and NIPBL interaction has unreplaceable roles in the distribution of cohesin complex component (Rad21) chromatin immunoprecipitation-seq peaks, occupancy of global Rad21 or CTCF at NIPBL loading sites, and ATP depletion biases cohesin localization toward NIPBL loading sites [3]. About 97% stripe domains appear in NIPBL and Rad21 recruitment. Different elements of noncoding genome are involved in regulation of the NIPBL gene, e.g. NIPBL-AS1 a long non-coding RNA antisense to NIPBL.
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Intergenic regions (R1 and R2) at 130 kb and 160 kb upstream of the NIPBL promoter, are considered as optimal candidates for a NIPBL distal enhancer and highly correlated with open chromatin and histone variants/marks at enhancers and active transcription [4]. Such distal enhancer can regulate expression of NIPBL, NIPBL-AS1, or diseasespecific genes. The regulation of the NIPBL gene is of great interest, since organisms are sensitive to NIPBL levels. NIPBL plays an important role in cancer cell proliferation, migration, and infiltration in the G0/ G1 phase of cell cycle, preventing from apoptosis or autophagy and generating cell resistance to drugs [5]. NIPBL is one of key factors to regulate process of CTCF and cohesin into chromatin loops and topologically associated domains (TADs), binding of cohesin with histone H3 lysine 4 trimethylation (H3K4me3) through interaction among promoters and enhancers, and 3D organization and dynamics of the genome [3,6–9]. The NIPBL- sister chromatid cohesion factor (MAU)4 complex controls loading of physically tethered cohesin rings at NIPBL sites of chromatin, extrudes along DNA, and halts at CTCF bound to inward-oriented motifs in the convergent orientation and opposite directions [3]. The present article overviews the critical and regulatory roles of NIBPL in cohesion loading on chromotin and in gene expression and transcriptional signaling. We explore molecular mechanisms by which NIPBL recruits endogenous histone deacetylase (HDAC) to
Corresponding author. E-mail address: [email protected] (X. Wang).
https://doi.org/10.1016/j.semcdb.2018.08.005 Received 20 July 2018; Accepted 6 August 2018 1084-9521/ © 2018 Elsevier Ltd. All rights reserved.
Please cite this article as: Gao, D., Seminars in Cell and Developmental Biology (2018), https://doi.org/10.1016/j.semcdb.2018.08.005
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induce histone deacetylation and influence multi-dimensions of genome, through which NIPBL “hop” movement in chromatin regulates gene expression and alters genome folding. 2. “Porter” role of NIPBL in cohesin loading on DNA NIPBL (also named CDLS, IDN3, SCC2, CDLS1, IDN3-B) encodes the homolog of Nipped-B like protein and colon tumor susceptibility 2-type sister chromatid cohesion proteins, to facilitate enhancer-promoter interaction of remote enhancers. During mitotic process, cohesin assistes in replicating chromatids and promoting the repair of DNA damage. NIPBL is indispensable during process of loading the cohesin complex onto DNA [10] and a core part of cohesin complex associated with stromal antigen subunit SA1 or SA2. Loss of cohesin integrity results in end-joining of distant DNA double strand breaks (DSBs) which is nonhomologous [11,12]. NIPBL and MAU2 heterodimer is comprised of a separate ‘loader’ complex to facilitate the initial association of cohesin with DNA. N- and C-terminals of NIPBL are pivotal to load dohesin on DSBs. Heterochromatin protein 1 (HP1) recruits NIPBL to DNA damage sites, and has three isoforms (HP1α, β, γ), of which HP1γ appears to retain the HP1 domain fragment at DNA damage. The N-terminus of NIPBL was recruited to DSBs through the corresponding HP1-binding motif, which was assisted by HP1γ. HP1 regulates the recruitment and accumulation of NipblN, probably through a motif binding to the Nterminus of NIPBL [10]. For example, HP1 binding motif and vitamin D receptor gene nuclease are required for the recruitment of NIPBLN to DNA damage [13]. HP1-mediated recruitment is independent upon MAU2, while requests the presence of ring finger protein (RNF)168 ubiquitin ligase in DNA damage-dependent RNF8/RNF168 signaling [13]. The sensor protein MDC1 recruits RNF8 to ubiquitinated histone H1 and then to RNF168, resulting in more potent histone H2A Soymilk [14–16]. The role and recruitment of NIPBL adhesion in DNA damage sites varies among types of impaired DNA. Through HEAT repeat domains, the recruitment of NIPBL C-terminal to DSBs is triggered by laser microirradiation. Recruitment approaches for NIPBL depend on the RNF8/RNF168 ubiquitylation pathway, where MDC1 recruits RNF8 to ubiquitinated histone H1, followed by RNF168, polyubiquitinated histone H2A, downstream to 53BP1, BRCA1, and mucin-associated structural maintenance of chromosomes (SMC)5/6 complexes [17–20]. In addition, ATM/ATR serine/threonine kinase activity is required in the C-terminal mediated recruitment of NIPBL. Cohesin is enriched in the endonuclease-derived flanking regions of protein coding debris buster and highly dependent upon the NIPBL/MAU2 loading subcomplex. NIPBL and MAU2 complexes loading to DSBs is a prerequisite for repairing the DNA damage through cohesin binding to DNA during separate "load" at the end of the cell [10,21,22]. Early components γH2AX and Mre11 produced in DNA damage response are also required for the accumulation of cohesin on DSBs. NIPBL plays a highly dynamic role in maintaining genetic stability and forms a complex in response to damaged DNA (Fig. 1). The sister chromatid cohesin (SCC) is established during S phase and plays a central role in accurate segregation of chromosome and efficient repair of DSBs. The chromosomes segregation and G2-phase DSB repair can be hardly achieved with cohesin [22].
Fig. 1. Cohesin loading factor (NIPBL)-dominant transcriptional reguations. Challenges. trigger DNA damage characterized by double strand breaaks (DSBs). The C- and N-terminals of NIPBL is recruited to DSBs, through HEAT repeat domain and the corresponding heterochromatin protein 1 (HP1)-binding motif, respectively, in assistance with HP1γ. The recruitment approaches for NIPBL depend on the ring finger protein (RNF)8/RNF168 ubiquitylation pathway. ATM/ATR activity is required in the C-terminal mediated recruitment of NIPBL in addition to RNF8/RNF168 ubiquitylation pathway.
physiological transit of NIPBL fused with MAU2 to the nucleus is a critical step of cell proliferation [5]. MAU2 as an chromatin linker targets NIPBL to specific chromosomal protein acceptor sites and acts as an independent role if NIPBL exists at the location of DNA damage [10]. MAC2 roles in recruitment of NIPBL can be replaced with distinct protein domains through different mechanisms of NIPBL recruitment. NIPBL isoforms accumulate on the debris buster and NIPBL and MAU2 heterodimer are recruited to damaged DNA, to play roles of adhesin loading in chromosome segregation during DNA repair [25,26]. Cohesin plays an important role in the formation of the chromosome structure that influences the gene expression. S-phase mucins and DSBinduced mucins play important roles in the process of SCC. Cohesin binding to chromosome promotes chromosome segregation and DNA repair, while adhesin proteins assist in the establishment of chromosomal boundaries, bind to mating loci, and limit the spread of gene silencing messages [27]. NIPBL is necessary for the aggregation of sister chromatids during meiosis, where meiotic recombination protein (REC8) encodes a specific adhesin subunit. At meiotic stage, REC8 activation, mucins, and annexin recruitment to the sister chromatid require the existence of NIPBL to promote the cohesin loading onto chromosome [28] and maintain levels of REC8 in meiotic cells. NIPBL enhances transcriptional activity of REC8 promoter through NIPBL and cohesin interaction during meiosis after REC8 mRNA production. REC8 was minimally mapped on meiotic chromosomes in depletion of NIPBL. Of 792 binding sites identified for NIPBL, majority sites are located on the meiotic chromosome for meiosis accompanied by sister chromosome [26]. NIPBL and MAU2 complex contributes to recruitment of adhesins to sister chromatid in chromosome, since cohesin regulates the proper concentration of chromosomes and promotes the formation of the chromosomal loops [29,30]. NIPBL and MAU2 complex promotes the extension of chromatin loops to form TADs as autonomous transcriptional units. Of the complex, MAC2 regulates the interaction with NIPBL and contact frequency between loop anchors. Cohesin release factor WAPL has the decisive role in control of MAC2 expression, MAC2-regulated length of extended loops [31]. WAPL restricts the loop formation between incorrect CTCF sites and is involved in the release of chromosomal loop through the open of a distinct DNA exit gate, when
3. Regulatory roles of NIPBL in gene expression Cohesin regulates gene expression and controls cell cycle, which is influenced with gene variants, SMC1A, SMC3, and HDAC 8 in cohesin complex [23]. The process of NIPBL variant recruitment to DNA damage is important for maintenance of 3D genome organization and initiation of repair and is associated with isoforms of NIPBL. NIPBL has A and B isoform at 316 and 304 kDa proteins, respectively. Responses of cells with different isoforms of NIPBL to DNA damage vary [24]. The 2
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differentiation stage-specific manner. Interactions are regulated by post-translational modifications or availability of interacting proteins, to recruit cohesin to multiple sites varied among cell types and provide further versatility fot actions. 4. NIPBL recruits endogenous HDAC to induce histone deacetylation Acetylated histones in mitosis induce chromosome structural defects and abnormal chromosome numbers such as aneuploidy [39]. When histones are highly acetylated during mitotic condensation, mitotic chromosomes with 3D structure are produced and chromatin remodeling is altered [40]. NIPBL can initiate deacetylation of lysine 9 of histone 3 (H3K9) for methylation and recruits HDACs to mediate local chromatin modifications [41]. It has been revealed that histone modifications affect cohesin recruitment to specific chromosomal loci. Acetylation of histone protein facilitates the dissociation of DNA, histone octamer, and relaxation of nucleosome structure. Various transcription factors and co-transcription factors specifically bind to DNA binding sites and activate gene transcription. NIPBL-binding proteins isolate chromatin-modifying cofactors by deacetylating histones or HDAC1 and HDAC3. NIPBL fused to the GAL4-DNA binding domain inhibits the promoter activity of numerous genes by recruitment of HDACs, which was reduced by the missense mutation of NIPBL in disease, due to HDAC inhibition [34]. 5. NIPBL “hops” among chromosomal loops NIPBL movement in chromatin regulates gene expression through alterations of chromosome organization. NIPBL is a hook protein with the N-terminal domain to bind with MAU2 and form cohesin-loaded complex [42]. NIPBL plays an essential role in cohesin loading onto chromosomes, rather than sister chromatids [43,44]. Cohesin complex mediates the process of DNA-DNA interactions between SCC and DNA loop. NIPBL-regulated cohesin loading onto chromosomes is initiated by stimulating cohesin ABC-like ATPase and post-loading function in driving loop extrusion. NIPBL binds dynamically to chromatin and moves within chromatin consistent with a’ stop-and-go’ or’ hopping’ motion [45,46] (Fig. 3). NIPBL, Pds5 and SCC3 (SA1/2) among HEAT repeat containing proteins associated with kleisins regulated the process of cohesin interactions with chromatin. For example, NIPBL regulates the initial interaction of cohesin with DNA with the assistance of ATP hydrolysis after stimulating cohesin ATPase [45,47–49]. NIPBL plays a role in TADs formation and cohesin loops loaded on chromosomes. As a hook protein about 316 kDa with the N-terminal domain, NIPBL binds to MAU2 and adhesins, forms adhesin-loaded complex for cohesin loading onto chromosomes, and acts as a potent activator of ATP hydrolysis by adhesins [50]. NIPBL binds NIPBL stimulates ATPases of adhesins, contributes to TADs formation, and transiently interact with chromosomes before and after DNA replication [51]. NIPBL is dissociated from chromatin in the early stages and eliminated from the chromosome during mitosis. NIPBL binds to chromatin more rapidly and frequently than dolastin with a residence time of 15–30 m [45]. The separation of NIPBL molecules from chromatin quickly reappears throughout the bleaching zone. The NIPBL diffused through or across the nucleus is severely slow, leading to the low mobility phenomenon [45]. Chemokines play an essential role in the binding of NIPBL to chromosomes. The increased rate of SCC1 degradation restored may slow down the diffusion of NIPBL in nucleu by interaction between NIPBL and soluble adhesin pools and jumping between adjacent chromosomal protein complexes [45]. One of outstanding studies performed by Rhodes et al desbribes NIPBL interactions and colocalizations with cohesin outside of the loading reaction using live cell imaging [45]. It seems that cohesion modulates the density of NIPBL dynamically rapidly during NIPBL
Fig. 2. Roles of NIPBL-cohesin interactions in genome stability. A: The cohesin complex loop together with CCCTC-binding factor (CTCF) sites forms into 3D genome, including processive enlargement of loops and polyclonal collections of loops shaping topologically associated domains (TADs). Nipbl stimulates cohesin ATPase and facilitate the formation of TADs [45]. B: The horizontal axis is the promoting role of NIPBL and sister chromatid cohesion factor (MAU)2 complex in loop extension, and the vertical axisrepresents the inhibiting role of cohesin release factor (WAPL), of which the balance plays important role in chromation stability. C: The difference of chromatin loop lengh exists in presence or absence of WAPL, which restricts the loop extension. D: Open of a distinct DNA exit gate at the interface interacts with cohesin mucin-associated structural maintenance of chromosomes (SMC)3 and sister chromatid cohesin (SCC)1 subunits. WAPL promotes cohesin release from chromatin.
ATPase conformation is changed at the interface with SMC3 and SCC1 (Fig. 2). WAPL contributes to regulation of loop length by increasing turnover of cohesin on chromation and decreasing contact frequency between cohesion, DNA and nearby TADs [32–34]. TADs are constituted of the cohesin complex loop with processive enlargement and polyclonal collections of CTCF site. The size of chromosomal loop is up-regulated with NIPBL/MAU2 complex and downregulated with WAPL. Stability of the loop is maintained by balance between NIPBL/MAU2 complex and WAPL (Fig. 2C) and cohesin colocalization with CTCF [31,35]. Adhesins are located on the chromosomal CTCF binding site, where cohesin acts as an insulator to block interaction between enhancer and corresponding promoter [36–38]. Increased binding of cohesin with NIPBL or MAU2 can trigger cohesin accumulation at specific genomic regions. Potential interaction surfaces on cohesin, NIPBL, and MAU2, may be targeted by interactions with sequence-specific transcription factors, chromatin remodelers, specific histone mark readers, and even with RNA. Of those interactions, many occur at a specific subcellular and/or genomic location in cell cycle or 3
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RNF168 ubiquitylation pathway. NIPBL plays an important role in cohesin loading on DNA and a highly dynamic role in maintaining genetic stability and forming the complex in response to damaged DNA. NIPBL contributes to regulation of genome-controlled gene expression through the influence of cohesin in chromosome structure. NIPBL interacts with cohesin and then increases transcriptional activities of REC8 promoter, leading to up-regulation of gene expression. NIPBL recruits endogenous HDAC to induce histone deacetylation during mitotic condensation and mediate modifications of local chromatins. NIPBL movement among chromosomal loops regulates gene expression through dynamic alterations of genome organization. NIPBL interacts with cohesin as a key chromatin organizer of genome functions in mitosis and interphase and is one of the most sensitive factors contributing to developmental processes [57]. NIPBL dysfunction has been suggested to be associated abnormality of chromosome condensation, reducing cohesin loading at the β-globin locus in embryonic liver and long-distance chromatin interactions [58]. It is questioned if NIPBL can be a biology- or disease-specific biomarker candidate measurable, repeatable, and targetable. It is questioned about the specificity of NIPBL in represidentive to cohesin function, CTCF binding, transcriptional regulation, disease severity, duration, and sensitivity to therapies [59–65]. In addition to the loading of cohesin or other SMC complexes [66], NIPBL with WAP1 control cohesin colocalization on the longitudinal axis of metaphase chromosomes depending upon ATPase activity. Specificity and regulatory function of NIPBL should be furthermore investigated in single cell level using technology of clustered regularly interspaced short palindromic repeats, to define roles of NIPBL in genome folding, gene expression, heterogeneity, phenomes, and sensitivity to therapy [67–72]. Thus, we expect a new and deep insight to understand dynamics of chromosome and explore potential strategies of therapiesc on basis of NIPBL.
Fig. 3. NIPBL movement within chromatin is a’ stop-and-go’ from a to b in the line A or’ hopping’ motion from b to c between lines A and B. NIPBL hops between cohesins loaded on DNA and ensures cohesin interactions with chromatin in binding modes. NIPBL is located in nuclur during interphase, dissociated from chromatin in prophase, and excluded from chromosomes during mitosis. Nipbl, pds5,scc3 regulate cohesin's association with chromatin and the first step of association between them is regulated by nipbl and also involve ATP hydrolysis [50,73]. Beyond CTCF binding sites, CTCF may prevent cohesin’s association with Nipbl, stop ATP hydrolysis by cohesin and halt extrusion of loops in line C [45].
movement between chromosomal cohesin complexes with special vicinity. NIPBL performs different functions from loading in a low stoichiometry relative to cohesin and a high affinity for chromosomal cohesion. Using timelapse confocal microscopy confirmed, NIPBL was found to be located in nucleu during interphase, dissociated from chromatin in prophase, and excluded from chromosomes during mitosis [52–54].
Acknowledgements The work was supportedby Zhongshan Distinguished Professor Grant (XDW), The National Nature Science Foundation of China (91230204, 81270099, 81320108001, 81270131, 81300010, 81700008), The Shanghai Committee of Science and Technology (12JC1402200, 12431900207, 11410708600, 14431905100), Operation funding of Shanghai Institute of Clinical Bioinformatics, Ministry of Education for Academic Special Science and Research Foundation for PhD Education (20130071110043), and National Key Research and Development Program (2016YFC0902400, 2017YFSF090207).
6. Roles of NIPBL in genome folding Compartment subtypes to megakaryocytoplasmic (TAD) and megabase-large active and inactive compartments play important roles in maintaining chromosome organization and genome folding [54], although it is still unclear how those are formed, interacted, and affectedin genome organization. NIPBL deletion in mouse liver resulted in a significant recombination of chromosome folding [55]. Key features of 3D structure in metazoans include TADs, compartmentalization, and peak interactions [56]. Cohesin plays decisive roles in loading of chromatin by adhesin-NIPBL/NIPBL in interphase chromatin, evidenced in loss of Nipb1 in non- dividing hepatocytes withour NIPBL by using a liver-specific tamoxifen-induced Cre driver [10]. Reduction of chromatin-induced adhesin induces transfer of laminin from chromatin fraction to soluble nuclear fraction indicates NIPBL/MAU2 complex promotes the formation of chromatin loop extensions and TADs [31,48] and balance between NIPBL/MAU2 and WAPL activities regulates cohesin contributions to correct structural formation of chromosomes. NIPBL/MAU2 complexes through which cohesin is loaded onto DNA, which is released by the LBD driven by the adhesion protein antagonist [42].
References [1] T. Mizuguchi, G. Fudenberg, S. Mehta, J.M. Belton, N. Taneja, H.D. Folco, P. FitzGerald, J. Dekker, L. Mirny, J. Barrowman, S.I.S. Grewal, Cohesin-dependent globules and heterochromatin shape 3D genome architecture in S. pombe, Nature 516 (2014) 432–435. [2] Z. Tang, O.J. Luo, X. Li, M. Zheng, J.J. Zhu, P. Szalaj, P. Trzaskoma, A. Magalska, J. Wlodarczyk, B. Ruszczycki, P. Michalski, E. Piecuch, P. Wang, D. Wang, S.Z. Tian, M. Penrad-Mobayed, L.M. Sachs, X. Ruan, C.L. Wei, E.T. Liu, G.M. Wilczynski, D. Plewczynski, G. Li, Y. Ruan, CTCF-mediated human 3D genome architecture reveals chromatin topology for transcription, Cell 163 (2015) 1611–1627. [3] L. Vian, A. Pekowska, S.S.P. Rao, K.R. Kieffer-Kwon, S. Jung, L. Baranello, S.C. Huang, L. El Khattabi, M. Dose, N. Pruett, A.L. Sanborn, A. Canela, Y. Maman, A. Oksanen, W. Resch, X. Li, B. Lee, A.L. Kovalchuk, Z. Tang, S. Nelson, M. Di Pierro, R.R. Cheng, I. Machol, B.G. St Hilaire, N.C. Durand, M.S. Shamim, E.K. Stamenova, J.N. Onuchic, Y. Ruan, A. Nussenzweig, D. Levens, E.L. Aiden, R. Casellas, The Energetics and Physiological Impact of Cohesin Extrusion, Cell 173 (2018) 1165–1178 e20. [4] J. Zuin, V. Casa, J. Pozojevic, P. Kolovos, M. van den Hout, W.F.J. van Ijcken, I. Parenti, D. Braunholz, Y. Baron, E. Watrin, F.J. Kaiser, K.S. Wendt, Regulation of the cohesin-loading factor NIPBL: Role of the lncRNA NIPBL-AS1 and identification of a distal enhancer element, PLoS Genet. 13 (2017) e1007137. [5] H. Zhou, L. Zheng, K. Lu, Y. Gao, L. Guo, W. Xu, X. Wang, Downregulation of Cohesin Loading Factor Nipped-B-Like Protein (NIPBL) Induces Cell Cycle Arrest, Apoptosis, and Autophagy of Breast Cancer Cell Lines, Med. Sci. Monit. 23 (2017)
7. Conclusions and perspectives NIPBL is one of important regulatory factors in the maintenance of 3D genome organization and function, by interacting with a large number of factors, e.g. cohesion, CTCF or Rad21. NIPBL regulates the process of CTCF and cohesion into chromatin loops and TADs, binding of cohesion and H3K4mes3 through interaction among promoters and enhancers. HP1 recruits NIPBL to DNA damage site through RNF8/ 4
Seminars in Cell and Developmental Biology xxx (xxxx) xxx–xxx
D. Gao et al.
[33] O. Crawley, C. Barroso, S. Testori, N. Ferrandiz, N. Silva, M. Castellano-Pozo, A.L. Jaso-Tamame, E. Martinez-Perez, Cohesin-interacting protein WAPL-1 regulates meiotic chromosome structure and cohesion by antagonizing specific cohesin complexes, Elife 5 (2016) e10851. [34] P. Jahnke, W. Xu, M. Wulling, M. Albrecht, H. Gabriel, G. Gillessen-Kaesbach, F.J. Kaiser, The Cohesin loading factor NIPBL recruits histone deacetylases to mediate local chromatin modifications, Nucleic Acids Res. 36 (2008) 6450–6458. [35] B.A. Bouwman, W. de Laat, Getting the genome in shape: the formation of loops, domains and compartments, Genome Biol. 16 (2015) 154. [36] S.J. Holwerda, W. de Laat, CTCF: the protein, the binding partners, the binding sites and their chromatin loops, Philos. Trans. R. Soc. Lond. B Biol. Sci. 368 (2013) 20120369. [37] M. Vietri Rudan, C. Barrington, S. Henderson, C. Ernst, D.T. Odom, A. Tanay, S. Hadjur, Comparative Hi-C reveals that CTCF underlies evolution of chromosomal domain architecture, Cell Rep. 10 (2015) 1297–1309. [38] A. Mora, G.K. Sandve, O.S. Gabrielsen, R. Eskeland, In the loop: promoter-enhancer interactions and bioinformatics, Brief Bioinf. 17 (2016) 980–995. [39] F. Yang, C. Baumann, M.M. Viveiros, R. De La Fuente, Histone hyperacetylation during meiosis interferes with large-scale chromatin remodeling, axial chromatid condensation and sister chromatid separation in the mammalian oocyte, Int. J. Dev. Biol. 56 (2012) 889–899. [40] E. Toselli-Mollereau, X. Robellet, L. Fauque, S. Lemaire, C. Schiklenk, C. Klein, C. Hocquet, P. Legros, L. N’Guyen, L. Mouillard, E. Chautard, D. Auboeuf, C.H. Haering, P. Bernard, Nucleosome eviction in mitosis assists condensin loading and chromosome condensation, EMBO J. 35 (2016) 1565–1581. [41] C. Pattaroni, C. Jacob, Histone methylation in the nervous system: functions and dysfunctions, Mol. Neurobiol. 47 (2013) 740–756. [42] T. Visnes, F. Giordano, A. Kuznetsova, J.A. Suja, A.D. Lander, A.L. Calof, L. Strom, Localisation of the SMC loading complex Nipbl/Mau2 during mammalian meiotic prophase I, Chromosoma 123 (2014) 239–252. [43] S. Remeseiro, A. Cuadrado, S. Kawauchi, A.L. Calof, A.D. Lander, A. Losada, Reduction of Nipbl impairs cohesin loading locally and affects transcription but not cohesion-dependent functions in a mouse model of Cornelia de Lange Syndrome, Biochim. Biophys. Acta 1832 (2013) 2097–2102 10.1098 /rsob.150178. [44] M. Ocampo-Hafalla, S. Munoz, C.P. Samora, F. Uhlmann, Evidence for cohesin sliding along budding yeast chromosomes, Open Biol. (2016) 6. [45] J. Rhodes, D. Mazza, K. Nasmyth, S. Uphoff, Scc2/Nipbl hops between chromosomal cohesin rings after loading, Elife 6 (2017). [46] C. Barrington, R. Finn, S. Hadjur, Cohesin biology meets the loop extrusion model, Chromosome Res. 25 (2017) 51–60. [47] S. Villa-Hernandez, R. Bermejo, Cohesin dynamic association to chromatin and interfacing with replication forks in genome integrity maintenance, Curr. Genet. (2018). [48] A. Lau, H. Blitzblau, S.P. Bell, Cell-cycle control of the establishment of mating-type silencing in S. Cerevisiae, Genes Dev. 16 (2002) 2935–2945. [49] Y. Murayama, F. Uhlmann, Biochemical reconstitution of topological DNA binding by the cohesin ring, Nature 505 (2014) 367–371. [50] P. Arumugam, S. Gruber, K. Tanaka, C.H. Haering, K. Mechtler, K. Nasmyth, ATP hydrolysis is required for cohesin’s association with chromosomes, Curr. Biol. 13 (2003) 1941–1953. [51] E.P. Nora, B.R. Lajoie, E.G. Schulz, L. Giorgetti, I. Okamoto, N. Servant, T. Piolot, N.L. van Berkum, J. Meisig, J. Sedat, J. Gribnau, E. Barillot, N. Bluthgen, J. Dekker, E. Heard, Spatial partitioning of the regulatory landscape of the X-inactivation centre, Nature 485 (2012) 381–385. [52] A. Pistocchi, G. Fazio, A. Cereda, L. Ferrari, L.R. Bettini, G. Messina, F. Cotelli, A. Biondi, A. Selicorni, V. Massa, Cornelia de Lange Syndrome: NIPBL haploinsufficiency downregulates canonical Wnt pathway in zebrafish embryos and patients fibroblasts, Cell Death Dis. 4 (2013) e866. [53] C.L. Tiang, Y. He, W.P. Pawlowski, Chromosome organization and dynamics during interphase, mitosis, and meiosis in plants, Plant Physiol. 158 (2012) 26–34. [54] W. Schwarzer, N. Abdennur, A. Goloborodko, A. Pekowska, G. Fudenberg, Y. LoeMie, N.A. Fonseca, W. Huber, C. HH, L. Mirny, F. Spitz, Two independent modes of chromatin organization revealed by cohesin removal, Nature 551 (2017) 51–56. [55] V. Parelho, S. Hadjur, M. Spivakov, M. Leleu, S. Sauer, H.C. Gregson, A. Jarmuz, C. Canzonetta, Z. Webster, T. Nesterova, B.S. Cobb, K. Yokomori, N. Dillon, L. Aragon, A.G. Fisher, M. Merkenschlager, Cohesins functionally associate with CTCF on mammalian chromosome arms, Cell 132 (2008) 422–433. [56] G. Fudenberg, N. Abdennur, M. Imakaev, A. Goloborodko, L.A. Mirny, Emerging evidence of chromosome folding by loop extrusion, Cold Spring Harb. Symp. Quant. Biol. 82 (2017) 45–55. [57] K. Kuleszewicz, X. Fu, N.R. Kudo, Cohesin loading factor Nipbl localizes to chromosome axes during mammalian meiotic prophase, Cell Div. 8 (2013) 12. [58] A.R. Ball Jr., Y.Y. Chen, K. Yokomori, Mechanisms of cohesin-mediated gene regulation and lessons learned from cohesinopathies, Biochim. Biophys. Acta 1839 (2014) 191–202. [59] L. Shi, M.Xu B Zhu, X. Wang, Selection of AECOPD-specific immunomodulatory biomarkers by integrating genomics and proteomics with clinical informatics, Cell Biol. Toxicol. 34 (2018) 109–123. [60] Y. Kawamura, J. Takouda, K. Yoshimoto, K. Nakashima, New aspects of glioblastoma multiforme revealed by similarities between neural and glioblastoma stem cells, Cell Biol. Toxicol. (2018), https://doi.org/10.1007/s10565-017-9420-y. [61] D. Long, T. Yu, X. Chen, Y. Liao, X. Lin, RNAi targeting STMN alleviates the resistance to taxol and collectively contributes to down regulate the malignancy of NSCLC cells in vitro and in vivo, Cell Biol. Toxicol. 34 (2018) 7–21. [62] D. Wu, X. Wang, H. Sun, The role of mitochondria in cellular toxicity as a potential drug target, Cell Biol. Toxicol. 34 (2018) 87–91.
4817–4825. [6] P. Szalaj, D. Plewczynski, Three-dimensional organization and dynamics of the genome, Cell Biol. Toxicol. (2018), https://doi.org/10.1007/s10565-018-9428-y. [7] R. Li, Y. Liu, Y. Hou, J. Gan, P. Wu, C. Li, 3D genome and its disorganization in diseases, Cell Biol. Toxicol. (2018), https://doi.org/10.1007/s10565-018-9430-4. [8] T. Ma, L. Chen, M. Shi, J. Niu, X. Zhang, X. Yang, K. Zhanghao, M. Wang, P. Xi, D. Jin, M. Zhang, J. Gao, Developing novel methods to image and visualize 3D genomes, Cell Biol. Toxicol. (2018). [9] T. Terabayashi, K. Hanada, Genome instability syndromes caused by impaired DNA repair and aberrant DNA damage responses, Cell Biol. Toxicol. (2018). [10] C. Bot, A. Pfeiffer, F. Giordano, D.E. Manjeera, N.P. Dantuma, L. Strom, Independent mechanisms recruit the cohesin loader protein NIPBL to sites of DNA damage, J. Cell. Sci. 130 (2017) 1134–1146. [11] A. Kojic, A. Cuadrado, M. De Koninck, D. Gimenez-Llorente, M. Rodriguez-Corsino, G. Gomez-Lopez, F. Le Dily, M.A. Marti-Renom, A. Losada, Distinct roles of cohesinSA1 and cohesin-SA2 in 3D chromosome organization, Nat. Struct. Mol. Biol. 25 (2018) 496–504. [12] R. Ciosk, M. Shirayama, A. Shevchenko, T. Tanaka, A. Toth, A. Shevchenko, K. Nasmyth, Cohesin’s binding to chromosomes depends on a separate complex consisting of Scc2 and Scc4 proteins, Mol. Cell 5 (2000) 243–254. [13] Y. Oka, K. Suzuki, M. Yamauchi, N. Mitsutake, S. Yamashita, Recruitment of the cohesin loading factor NIPBL to DNA double-strand breaks depends on MDC1, RNF168 and HP1gamma in human cells, Biochem. Biophys. Res. Commun. 411 (2011) 762–767. [14] T. Thorslund, A. Ripplinger, S. Hoffmann, T. Wild, M. Uckelmann, B. Villumsen, T. Narita, T.K. Sixma, C. Choudhary, S. Bekker-Jensen, N. Mailand, Histone H1 couples initiation and amplification of ubiquitin signalling after DNA damage, Nature 527 (2015) 389–393. [15] C. Doil, N. Mailand, S. Bekker-Jensen, P. Menard, D.H. Larsen, R. Pepperkok, J. Ellenberg, S. Panier, D. Durocher, J. Bartek, J. Lukas, C. Lukas, RNF168 binds and amplifies ubiquitin conjugates on damaged chromosomes to allow accumulation of repair proteins, Cell 136 (2009) 435–446. [16] G.S. Stewart, S. Panier, K. Townsend, A.K. Al-Hakim, N.K. Kolas, E.S. Miller, S. Nakada, J. Ylanko, S. Olivarius, M. Mendez, C. Oldreive, J. Wildenhain, A. Tagliaferro, L. Pelletier, N. Taubenheim, A. Durandy, P.J. Byrd, T. Stankovic, A.M. Taylor, D. Durocher, The RIDDLE syndrome protein mediates a ubiquitindependent signaling cascade at sites of DNA damage, Cell 136 (2009) 420–434. [17] M.S. Huen, R. Grant, I. Manke, K. Minn, X. Yu, M.B. Yaffe, J. Chen, RNF8 transduces the DNA-damage signal via histone ubiquitylation and checkpoint protein assembly, Cell 131 (2007) 901–914. [18] N. Mailand, S. Bekker-Jensen, H. Faustrup, F. Melander, J. Bartek, C. Lukas, J. Lukas, RNF8 ubiquitylates histones at DNA double-strand breaks and promotes assembly of repair proteins, Cell 131 (2007) 887–900. [19] N.K. Kolas, J.R. Chapman, S. Nakada, J. Ylanko, R. Chahwan, F.D. Sweeney, S. Panier, M. Mendez, J. Wildenhain, T.M. Thomson, L. Pelletier, S.P. Jackson, D. Durocher, Orchestration of the DNA-damage response by the RNF8 ubiquitin ligase, Science 318 (2007) 1637–1640. [20] M. Raschle, G. Smeenk, R.K. Hansen, T. Temu, Y. Oka, M.Y. Hein, N. Nagaraj, D.T. Long, J.C. Walter, K. Hofmann, Z. Storchova, J. Cox, S. Bekker-Jensen, N. Mailand, M. Mann, DNA repair. Proteomics reveals dynamic assembly of repair complexes during bypass of DNA cross-links, Science 348 (2015) 1253671. [21] L. Strom, H.B. Lindroos, K. Shirahige, C. Sjogren, Postreplicative recruitment of cohesin to double-strand breaks is required for DNA repair, Mol. Cell 16 (2004) 1003–1015. [22] E. Watrin, J.M. Peters, Cohesin and DNA damage repair, Exp. Cell Res. 312 (2006) 2687–2693. [23] J. Pozojevic, I. Parenti, L. Graul-Neumann, S. Ruiz Gil, E. Watrin, K.S. Wendt, R. Werner, T.M. Strom, G. Gillessen-Kaesbach, F.J. Kaiser, Novel mosaic variants in two patients with Cornelia de Lange syndrome, Eur. J. Med. Genet. (2017), https:// doi.org/10.1016/j.ejmg.2017.11.004. [24] C. Lukas, F. Melander, M. Stucki, J. Falck, S. Bekker-Jensen, M. Goldberg, Y. Lerenthal, S.P. Jackson, J. Bartek, J. Lukas, Mdc1 couples DNA double-strand break recognition by Nbs1 with its H2AX-dependent chromatin retention, EMBO J. 23 (2004) 2674–2683. [25] I. Litwin, R. Wysocki, New insights into cohesin loading, Curr. Genet. 64 (2018) 53–61. [26] J.M. Peters, T. Nishiyama, Sister chromatid cohesion, Cold Spring Harb. Perspect. Biol. 4 (2012). [27] B.D. Eads, D. Tsuchiya, J. Andrews, M. Lynch, M.E. Zolan, The spread of a transposon insertion in Rec8 is associated with obligate asexuality in Daphnia, Proc. Natl Acad. Sci. U. S. A. 109 (2012) 858–863. [28] S. Burkhardt, M. Borsos, A. Szydlowska, J. Godwin, S.A. Williams, P.E. Cohen, T. Hirota, M. Saitou, K. Tachibana-Konwalski, Chromosome cohesion established by Rec8-Cohesin in fetal oocytes is maintained without detectable turnover in oocytes arrested for months in mice, Curr. Biol. 26 (2016) 678–685. [29] J. Dekker, E. Heard, Structural and functional diversity of topologically associating domains, FEBS Lett. 589 (2015) 2877–2884. [30] J. Gassler, H.B. Brandao, M. Imakaev, I.M. Flyamer, S. Ladstatter, W.A. Bickmore, J.M. Peters, L.A. Mirny, K. Tachibana, A mechanism of cohesin-dependent loop extrusion organizes zygotic genome architecture, EMBO J. 36 (2017) 3600–3618. [31] J.H.I. Haarhuis, R.H. van der Weide, V.A. Blomen, J.O. Yanez-Cuna, M. Amendola, M.S. van Ruiten, P.H.L. Krijger, H. Teunissen, R.H. Medema, B. van Steensel, T.R. Brummelkamp, E. de Wit, B.D. Rowland, The cohesin release factor wapl restricts chromatin loop extension, Cell 169 (2017) 693–707 e14. [32] A.L. Marston, Chromosome segregation in budding yeast: sister chromatid cohesion and related mechanisms, Genetics 196 (2014) 31–63.
5
Seminars in Cell and Developmental Biology xxx (xxxx) xxx–xxx
D. Gao et al.
[69] H. Devine, R. Patani, The translational potential of human induced pluripotent stem cells for clinical neurology : The translational potential of hiPSCs in neurology, Cell Biol. Toxicol. 33 (2017) 129–144. [70] W. Wang, B. Zhu, X. Wang, Dynamic phenotypes: illustrating a single-cell odyssey, Cell Biol. Toxicol. 33 (2017) 423–427. [71] M.P. Chu, J. Kriangkum, C.P. Venner, I. Sandhu, J. Hewitt, A.R. Belch, L.M. Pilarski, Addressing heterogeneity of individual blood cancers: the need for single cell analysis, Cell Biol. Toxicol. 33 (2017) 83–97. [72] D.C. Wang, W. Wang, B. Zhu, X. Wang, Lung cancer heterogeneity and new strategies for drug therapy, Annu. Rev. Pharmacol. Toxicol. 58 (2018) 531–546. [73] J.N. Wells, T.G. Gligoris, K.A. Nasmyth, J.A. Marsh, Evolution of condensin and cohesin complexes driven by replacement of Kite by Hawk proteins, Curr. Biol. 27 (2017) R17–R18.
[63] X. Liu, J. Wu, History, applications, and challenges of immune repertoire research, Cell Biol. Toxicol. (2018), https://doi.org/10.1007/s10565-018-9426-0. [64] L. Shi, N. Dong, D. Ji, X. Huang, Z. Ying, X. Wang, C. Chen, Lipopolysaccharideinduced CCN1 production enhances interleukin-6 secretion in bronchial epithelial cells, Cell Biol. Toxicol. 34 (2018) 39–49. [65] M. Xu, X. Wang, Critical roles of mucin-1 in sensitivity of lung cancer cells to tumor necrosis factor-alpha and dexamethasone, Cell Biol. Toxicol. 33 (2017) 361–371. [66] T. Gligoris, J. Lowe, Structural Insights into Ring Formation of Cohesin and Related Smc Complexes, Trends Cell Biol. 26 (2016) 680–693. [67] W. Wang, X. Wang, Single-cell CRISPR screening in drug resistance, Cell Biol. Toxicol. 33 (2017) 207–210. [68] T. Sakuma, T. Yamamoto, Magic wands of CRISPR-lots of choices for gene knock-in, Cell Biol. Toxicol. 33 (2017) 501–505.
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