DNA damage-induced inflammation and nuclear architecture

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Original Article

DNA damage-induced inflammation and nuclear architecture Kalliopi Stratigi a , Ourania Chatzidoukaki a , George A. Garinis a,b,∗ a b

Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, Nikolaou Plastira 100, 70013, Heraklion, Crete, Greece Department of Biology, University of Crete, Vassilika Vouton, GR71409, Heraklion, Crete, Greece

a r t i c l e

i n f o

Article history: Received 24 June 2016 Received in revised form 20 September 2016 Accepted 25 September 2016 Available online xxx Keywords: DNA damage Nuclear architecture Innate immunity Inflammation

a b s t r a c t Nuclear architecture and the chromatin state affect most–if not all- DNA-dependent transactions, including the ability of cells to sense DNA lesions and restore damaged DNA back to its native form. Recent evidence points to functional links between DNA damage sensors, DNA repair mechanisms and the innate immune responses. The latter raises the question of how such seemingly disparate processes operate within the intrinsically complex nuclear landscape and the chromatin environment. Here, we discuss how DNA damage-induced immune responses operate within chromatin and the distinct sub-nuclear compartments highlighting their relevance to chronic inflammation. © 2016 Elsevier Ireland Ltd. All rights reserved.

1. Introduction

2. DNA sensing

The gradual accumulation of DNA lesions interferes with vital cellular processes such as DNA replication and transcription leading to cellular malfunction and tissue degeneration that threaten organismal survival (Garinis et al., 2008). To avoid the destructive course of DNA damage, cells are equipped with a battery of partially overlapping DNA repair mechanisms ensuring that the genetic information is preserved and faithfully transmitted into progeny. The last decade, a series of functional links between distinct factors involved in DNA repair and immune response have emerged (Chatzinikolaou et al., 2014; Karakasilioti et al., 2013; Brzostek-Racine et al., 2011). DNA (damage) sensors are now known to identify damaged self-DNA in the nucleus to recruit the DNA repair machinery at sites of DNA damage but also activating “nuclear-to-cytoplasmic” signals that trigger an immune response (Chatzinikolaou et al., 2014). The latter supports the notion that the immune system may well recognize a “damaged cell” based on the physicochemical properties of the DNA itself.

In vertebrates, non-self, microbial products, such as the pathogen-associated molecular pattern molecules (PAMPS) and self-by-products, such as the damage- or otherwise stress-induced damage-associated molecular pattern molecules (DAMPS), are recognized by germline-encoded pattern recognition receptors (PRRs) that mount an appropriate immune response (Tang et al., 2012). Besides cell-surface and endosomal PRRs, cytosolic sensing receptors are capable of identifying DNA in the cytoplasm and initiate an immune response (Fig. 1A) (Paludan and Bowie, 2013; Barber, 2011; Wu and Chen, 2014). For instance, toll-like receptor (TLR) 9 is known to recognize CpG DNA and to activate the transcription of pro-inflammatory cytokines, such as the tumor necrosis factor alpha (TNF␣), interleukin (IL) 1 and IL6 and the type I interferons (IFNs), in a myeloid differentiation primary response gene 88 (MyD88), nuclear factor kappa B (NF-␬B) and IFN-regulatory factor (IRF) 7–dependent manner (Barber, 2011; Hemmi et al., 2000). The type I IFN response is also activated by the cyclic GMP-AMP synthase (cGAS) coupled to the stimulator of IFN genes (STING) − IRF3 pathway (Burdette et al., 2011; Sun et al., 2013) which functions as a non-redundant cytosolic DNA sensor (Li et al., 2013a). In parallel, the absent in melanoma (AIM) 2 induces the Apoptosis-associated speck-like protein containing a CARD (ASC)/Caspase 1 inflammasome pathway and the production of IL-1␤ (Hornung et al., 2009; Man and Kanneganti, 2015). DNA sensing in the nucleus refers mostly to DNA damage sensors detecting lesions that are generated during DNA replication or exposure of the genome to metabolic by-products e.g. free radicals

∗ Corresponding author at: Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, Nikolaou Plastira 100, 70013, Heraklion, Crete, Greece. E-mail address: [email protected] (G.A. Garinis). http://dx.doi.org/10.1016/j.mad.2016.09.008 0047-6374/© 2016 Elsevier Ireland Ltd. All rights reserved.

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Fig. 1. Nuclear architecture in DNA damage-induced inflammation. (A) DNA sensors (e.g. TLR9, cGAS, STING, DNA-PK) in the cytoplasm/nucleus detect (damaged) DNA and induce the transcription of pro-inflammatory cytokines. (B) Nuclear lamina-associated proteins (e.g. lamin A, lamin B1, nesprin1, BAF, SUN1/2, HP1) are involved in DNA repair and affect the DNA mobility and repair kinetics, causing immunerelated symptoms. (C) Nucleo-cytoplasmic trafficking of DNA repair and transcription factors through the nuclear pores promotes the DNA damage-induced inflammatory phenotype. (D) Nucleolar proteins (e.g. NCL, NPM) take part in DNA repair mechanisms and trigger the release of pro-inflammatory cytokines. (E) Apart from the intrinsic immune role of PML nuclear bodies, they also function as DNA damage sensors upon genotoxic insults. (F) The radial distribution of chromosome territories in the nucleus, as well as the level of chromatin compaction, affect, besides transcription, the DNA accessibility to damage and the DNA repair kinetics. (G) The involvement of DNA repair factors (e.g. PARP-1, XPG, XPF) in long range chromosomal interactions, DNA looping and nucleosome repositioning provide an additional level of regulation of DDR-induced inflammation.

or exogenous genotoxic insults induced by e.g. UV or ionizing irradiation. Subsequently, the cells have developed multiple DNA repair mechanisms to respond to each category (Table 1). Briefly, a battery of specialized DNA damage sensors recognize base modifications, bulky DNA adducts or DNA double strand breaks (DSBs) that trigger a DNA damage response (DDR) aimed at preferential mobilizing appropriate DNA repair mechanisms to restore damaged DNA back to its native form. For the highly cytotoxic DNA double strand breaks (DSBs), the meiotic recombination 11 homolog A (MRE11)/Rad50-Nbs1 (MRN) is considered the primary recognition protein complex (Grenon et al., 2001). Instead, bulky DNA lesions are primarily recognized by the XPC-RAD23-CETN2 complex (Masutani et al., 1994; Nishi et al., 2005). In other instances, it is the MutS proteins or the DNA glycosylases that detect mismatched or damaged bases, respectively (Krokan and Bjoras, 2013a; Pena-Diaz and Jiricny, 2012). Once DNA lesions are detected, the DDR signal is further amplified through a cascade of protein kinase reactions primarily initiated by the ATM (Ataxia telangiectasia, mutated) and/or ATR (ATM- and Rad3-related) protein kinases (Abraham, 2001; Shiloh and Kastan, 2001).

Interestingly, sensing of DNA either in the cytoplasm or the nucleus appears to mobilize partially overlapping mechanisms and protein factors. For instance, DNA-dependent protein kinase (DNAPK) (Ferguson et al., 2012), MRE11/RAD50 (Kondo et al., 2013) and Interferon gamma-Inducible protein (IFI) 16 (Ouchi and Ouchi, 2008; Unterholzner et al., 2010) are now considered to function both in sensing cytosolic DNA as well as DDR mediators. It would, thus, be interesting to test how such DNA sensors function upon various stress conditions, cellular compartments or even in tissues with distinct developmental origin, proliferative or regenerative capacities.

3. Damage-associated inflammatory phenotype The immediate removal of various foreign or self DNA species from cells is imperative for their viability. Failure to do so may often trigger a robust immune stimulation that in the long run may lead to chronic inflammation or the onset of autoimmune disorders. To prevent aberrant DNA-driven (auto)immune reactions, cells employ a battery of DNases, such as the DNase I in extracel-

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Table 1 DNA repair mechanisms. Repair mechanism

Damage sensor

Proteins implicated

Mechanism description

Ref.

Nucleotide Excision Repair (NER)

XPC/HRD23B/CENT2 (GG-NER), stalled RNA polymerase II (TC-NER)

UV-DDB (DDB1-XPE), CSA/CSB, TFIIH, XPB, XPD, XPA, RPA, XPG, ERCC1-XPF, DNA polymerase ␦ or ␧

Kamileri et al. (2012), Marteijn et al. (2014), Petruseva et al. (2014)

Base Excision Repair (BER)

DNA glycosylases

APE1, XRCC1, PNKP, Tdp1, APTX, DNA polymerase ␤, FEN1, DNA polymerase ␦ or ␧, PCNA-RFC, PARP

Homologous Recombination (HR)

Mre11-Rad50-Nbs1, CtlP

RPA, RAD51, RAD52, BRCA1, BRCA2, Exo1, BLM-TopIIa, GEN1-Yen1, Slx1-Mus81/Eme1

Non-Homologous End Joining (NHEJ)

Ku70-Ku80

DNA-PKc, XRCC4-DNA ligase IV, XLF

MisMatch Repair (MMR)

MutS␣, MutS␤

MutL␣, MutL␤, MutL␥, Exo1, PCNA-RFC

Interstrand Cross-Link repair (ICL)

UHRF1

FANCD2/FANCI, BRCA1, BRCA2, PALB2, XPF, MUS81

The NER pathway involves around 30 proteins and is divided into two subpathways, the Global Genome NER (GG-NER) and the Transcription Coupled NER (TC-NER), differing only at the recognition step. The GG-NER removes lesions throughout the genome whereas the TC-NER removes lesions only from the transcribed regions of the genome. BER is an enzymatic cascade responsible for the removal of a damaged DNA base. It involves the removal of the damaged base, the creation of a single strand break (nick), the inscision of the phosphodiester bond and the formation of a break with 3’ and 5’ blocking lesions. DNA processing enzymes repair the impaired termini and DNA synthesis and ligation finalize the process. The homologous recombination pathway is an error-free mechanism that uses the undamaged sister chromatid as a template for repair. It occurs at the the late-S and G2 phase of the cell cycle including the following steps: the presynapsis, the synapsis and the postsynapsis. The NHEJ process comprises of the DSB recognition by the Ku complex, the binding of the DNA-PKs to the DSB ends, the end processing and a final ligation step. MMR constitutes a highly conserved mechanism that facilitates the rectification of replication polymerases’ misproofreading. The mechanism can be divided into three steps: the mismatch recognition, the excision of the lesion and the gap filling. Depending on the phase of the cell cycle the interstrand crosslinks can be repaired with HR or NHEJ or Fanconi anemia pathway. In the occasion of the Fanconi anemia pathway the UHRF1 interacts with the ICLs and recruits the FANCD2/FANCI that leads to further recruitment of factors and ICL repair.

lular space, the DNase II in endolysosomes or TREX1 (DNase III) in the cytoplasm that are responsible for the immediate degradation of DNA by-products before the DNA sensing pathways are activated (Atianand and Fitzgerald, 2013). The significance of DNases in mammals is highlighted by a number of inborn defects in DNase I causing systemic lupus erythematosus (SLE)-like diseases (Napirei et al., 2000; Yasutomo et al., 2001), in DNase2a−/− mice that manifest constitutive production of IFN-␤, anaemia and embryonic death (Kawane et al., 2006, 2010; Yoshida et al., 2005) and mutations in TREX1 (DNase III) that are associated with the AicardiGoutières syndrome, a type I IFN autoimmune disease (Crow et al., 2006; Lee-Kirsch et al., 2007; Miyazaki et al., 2014; Morita et al., 2004; Stetson et al., 2008). Besides PRR signaling, the DDR may also promote a pro-inflammatory phenotype. Indeed, the functional links between irreparable DNA lesions, persistent DDR signaling and the activation of innate immune responses are particularly evident in NER-deficient patients and accompanying mouse models; intriguingly, NER patients present a DNA damage-driven proinflammatory senescence-associated secretory phenotype (SASP)

Kim and Wilson (2012), Krokan and Bjoras (2013b)

Jasin and Rothstein (2013), Li and Heyer (2008)

Davis and Chen (2013), Lieber (2008), Weterings and Chen (2008)

Hsieh and Yamane (2008), Li (2008)

Deans and West (2011), Liang et al. (2015)

(Rodier et al., 2009) that is thought to be causal to certain progeroid symptoms that markedly resemble those seen in autoimmune disorders. There are distinct phenotypic similarities between patients with AGS and patients with trichothiodystrophy (TTD; mutations in ERCC6/CSB or ERCC3/XPB and XPD) and with Cockayne syndrome (CS; mutations in ERCC8/CSA or ERCC6/CSB), emerging from similar neuropathology and type I IFN immune responses in these patients (Weiner and Gray, 2013; Brooks et al., 2008). Besides their role in the repair of DSBs, certain proteins involved in HR or the NHEJ repair pathways are also involved in immune activation. For instance, DNA-PK and MRE11 may trigger the expression of IFN-␤ through the STING-TBK1-IRF3 signaling cascade (Ferguson et al., 2012; Kondo et al., 2013); in support, loss of DNA-PK leads to severe immunodeficiency (Gao et al., 1998). Moreover, RAD50 is known to interact with the innate immune system adaptor CARD9 to produce IL-1␤ (Roth et al., 2014). Immunological symptoms are also presented in AP endonuclease (APE) 2-deficient mice (Guikema et al., 2007, 2014) and in mice lacking the 8oxoguanine-DNA glycosylase (OGG) 1 involved in base excision

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repair (da Silva et al., 2011; Touati et al., 2006). Besides their role in innate immune activation, certain DSB proteins have essential roles in nuclear processes that are critical for the diversity of T or B cells and for the effective adaptive immunity, such as the V(D)J recombination, class-switch recombination and somatic hypermutation (SHM) (Chaudhuri and Alt, 2004; Stavnezer et al., 2008; Xu, 2006). This is particularly evident in Ataxia telangiectasia (AT) patients associated with impaired DDR and pronounced immunodeficiency symptoms leading to increased susceptibility to infections (O’Driscoll and Jeggo, 2002); the latter underlines the central role of ATM kinase in mediating inflammation-driven responses (Figueiredo et al., 2013; Lavin, 2008). In other instances, defects in NHEJ are causal to severe combined immunodeficiency (SCID) (Woodbine et al., 2014). Besides the defects in DNA repair, persistent DNA damage signaling may also occur as a result of gradual telomere attrition with advancing age. Erosion of telomeres is now known to be causal to chronic inflammation. The latter is often attributed to the continuous activation of the immune system and the release of pro-inflammatory factors from senescent or damaged cells triggering the chronic infiltration of immune cells in various organs, increased vasculature and extensive fibrosis. Indeed, the presence of chronically inflamed tissues is thought to underlie a number of pathological symptoms associated with accelerated or natural ageing, including cancer, diabetes, and atherosclerosis (Freund et al., 2010). Recent data suggest that the induction of SASP relies on the involvement of transcription factors, the inflammasome and several non-coding RNAs (Olivieri et al., 2013); for example, NF-␬B and C/EBP␤ are known to induce the transcription of pro-inflammatory cytokines, such as TNF␣, IL-6, IL-1␣ or CXCL1, non-coding RNAs, like miR-155 that trigger the pro-inflammatory response and, together with the inflammasome, further propagate chronic inflammation. In turn, the proinflammatory secretome contributes to an efficient autocrine growth arrest and to the paracrine recruitment of immune cells aimed for clearance of senescent cells. However, although the inflammatory SASP originates from a protective tumor-suppressing response, it has long-term deleterious effects for the tissue microenvironment. These diverse effects of the SASP depend on the initiating signal and the receiving microenvironment of the neighboring cells, require DDR activation and include pro-tumorigenic invasion and vascularization, and senescence reinforcement (Freund et al., 2010; Lasry and Ben-Neriah, 2015). Taken together, DDR signaling and immune activation are closely intertwined. Using approaches to dissect the common players between DDR and immune responses will give us insights on how distinct stimuli e.g. DNA damage, viral or microbial infections are selectively recognized and how such mechanisms may be further explored for the development of rationalized intervention strategies.

4. Nuclear organization in DNA repair and DDR-induced inflammation The immune response against microbial and non-microbial pathogens requires the coordinated activity of transcription factors to express distinct subsets of genes in a cell-type and stimulusspecific dependent manner. The highly compartmentalized nucleus and chromatin organization provide an additional and crucial level of gene regulation, resulting in the non-random arrangement of gene loci in chromosome territories, the discrete nuclear foci of proteins/RNA, of subtle, reversible inter- and intra-chromosomal interactions and finally of nucleo-cytoplasmic trafficking events that mediate transcription. As with any DNA-dependent transaction, DNA repair itself is also affected by the nuclear architecture (Fig. 1) (Misteli and Soutoglou,

2009); the previously proposed “access-repair-restore” mechanism of DNA repair factors relies heavily on the spatial and temporal coordination of nuclear and chromatin environment (Polo and Almouzni, 2015). For instance, the various DNA repair factors are recruited to sites of DNA damage and in doing so such proteins also interact with distinct nuclear compartments. Moreover, the nuclear envelope, as well as the continuous nucleo-cytoplasmic shuttling of DDR- and immune-related factors, also play pivotal roles in gene regulation. It may, therefore, be of great interest to address DDR-driven pro-inflammatory responses in the context of chromatin dynamics and nuclear architecture.

5. Subnuclear compartments in DDR: the nuclear envelope In mammalian cells, the nucleus consists of distinct compartments, where specific protein factors are preferentially found, to ensure higher efficiency of vital, often overlapping DNA-dependent processes, such as transcription and DNA replication (Misteli, 2007). Evidence in yeast suggests that persistent DSBs migrate to the nuclear periphery and that DNA repair is spatially restricted in preferential repair centers arguing for DNA repair taking place in specialized repair foci whose efficiency in DNA damage removal is affected by the subnuclear micro-environment that the DNA lesion is found (Nagai et al., 2008; Taddei and Gasser, 2006; Oza et al., 2009). Contrary to the peripheral migration of DSBs and their association to the nuclear pore for repair in yeast, DSBs in mammalian cells are repaired individually in situ (Soutoglou et al., 2007; Aten et al., 2004; Nelms et al., 1998; Dion and Gasser, 2013). Often, the location of DNA lesions within the nucleus affects the chosen DNA repair pathway. For example, DSBs induced within laminassociated domains (LADs) are preferentially repaired by NHEJ or alternative end-joining rather than migrating to HR-permissive environments (Fig. 1B) (Lemaitre and Soutoglou, 2015; Lemaitre et al., 2014); this is likely because the heterochromatin in the nuclear lamina is thought to significantly delay the DDR (Goodarzi et al., 2010). This is in line with the reduced mobility of genomic loci associated with the nuclear lamina (Chubb et al., 2002), the inhibition of DSB movement by lamin A (Mahen, 2013) and the positional tethering of broken chromosomes by the DNA-end binding factor Ku80 (Soutoglou et al., 2007; Iarovaia et al., 2014). Alternatively, 53BP1, a major component of DNA damage foci, has been shown to promote NHEJ repair of deprotected telomeres and AID-induced breaks in immunoglobulin class-switch recombination (CSR), by facilitating the mobility of distant sites (Dimitrova et al., 2008). Positional immobility could, thus, prove to be dependent on the type of DNA damage, the cell type or the transcription status of the gene. In line, specific genetic loci radially relocate within the nuclear space of activated immune cells in a cell-type and genespecific manner (Solinhac et al., 2011; Gazave et al., 2005; Kolbl et al., 2012). Further evidence for the role of nuclear lamina in DNA repair is provided by studies in Nesprin 1-deficient cells; in these cells, the decreased activation of checkpoint kinases Chk1 and Chk2 impairs DDR (Sur et al., 2014). Besides the Nesprin 1-MSH2/MSH6 interactions, the DNA repair factors poly (ADP-ribose) polymerase 1 (PARP1), retinoblastoma-binding protein 4 (RBBP4), damagespecific DNA binding protein 1 (DDB1) and DDB2 were recently shown to interact with the barrier-to-autointegration factor (BAF) (Fig. 1B) (Montes de Oca et al., 2009). Moreover, deletion of the inner nuclear envelope SUN1/2 genes results in decreased ChK1 and ATM activation and the accumulation of irreparable DNA lesions in mice (Lei et al., 2012). The functional links between the nuclear envelope and the process of DNA repair are also prominent in the progeroid disorders (Oberdoerffer and Sinclair, 2007). The Hutchinson-Gilford progeria syndrome (HGPS) caused by a

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mutation in the lmna gene, encoding lamin A, shows similarities to Werner syndrome (WS) associated with a defect in WRN/RecQ helicase leading to a highly unstable genome (Scaffidi and Misteli, 2006; Pichierri et al., 2011). Cells derived from patients with HGPS show dysmorphic nuclei, nuclear membrane abnormalities and loss of heterochromatin-related proteins like heterochromatin protein 1 (HP1) (Scaffidi and Misteli, 2006, 2005). Besides any observed defects in nuclear shape, cells of HGPS patients rapidly accumulate DNA lesions likely due to the delayed recruitment of 53BP1 and Rad51 to site of damage (Liu et al., 2005), or else due to a decrease in Rad51 and Brca1 mRNA levels by loss of lamin A (Redwood et al., 2011). Genome instability and cellular senescence are further reinforced by elevated levels of reactive oxygen species present in lamin A-deficient cells (Peinado et al., 2011; Richards et al., 2011; Verstraeten et al., 2009). Moreover, lamin A-deficiency has been shown to affect the linker of nucleoskeleton and cytoskeleton (LINC) complex, critical for immunological synapse formation and impair T cell activation, consistent with the age-related defects in thymic development of lmna−/− mice (Gonzalez-Granado, 2014). Further links between nuclear architecture, the activation of immune responses and DNA repair itself come from the only known disease associated with lamin B1, namely the adult-onset autosomal dominant leukodystrophy (ADLD). In ADLD, the overexpression of lamin B1 results in the disorganization of inner nuclear membrane proteins and of chromatin, causing symptoms similar to multiple sclerosis and autoimmune diseases (Ferrera et al., 2014; Padiath and Fu, 2010). Instead, silencing of lamin B1 in tumor cells causes a delayed response to UV-induced DDR. In support, several NER factors, including DDB1, CSB and PCNA are downregulated in lamin B1-silenced cells, while the DSB-processing MRN complex assembly is impaired (ButinIsraeli et al., 2013, 2015). Ataxia telangiectasia (AT), like WS and HGPS, is also characterized by a defective nuclear architecture, genomic instability, progressive neurological symptoms and premature ageing (Lavin, 2008). Besides the defect in DDR, mutations in ATM also affect the interactions of telomeres to the nuclear matrix that may contribute to the early onset of progeroid features (Pandita, 2002; Smilenov et al., 1999).

6. Subnuclear compartments in DDR: the nuclear pore and nucleo-cytoplasmic trafficking Trafficking of proteins or RNA molecules across the nuclear membrane occurs through the nuclear pore complex (NPC), a multisubunit complex consisting of ∼30 nucleoporins (Nups), whose combination depends on the types of cells or tissues involved (reviewed in Raices and D’Angelo (2012), Wente and Rout (2010)). Efficient signal-dependent targeting of proteins in or out of the nucleus is mediated by the importin (IMPs) superfamily of transporters and the exportins (EXPs). Besides the tethering of DSBs to the NPCs in yeast (Nagai et al., 2008), translocation of various proteins takes place from the cytoplasm to the nucleus and vice versa in mammals, in response to DNA damage and stress signals (Fig. 1C). Examples include DNA damage sensors such as the MRN complex (Carney et al., 1998; Desai-Mehta et al., 2001), transcription factors like the NF-␬B (Wu and Miyamoto, 2007) and IRF1 (Frontini et al., 2009), the tumor-suppressor protein p53 (Fritsche et al., 1993), the apoptotic protease activating factor 1 (Apaf-1) (Jagot-Lacoussiere et al., 2015) or actin (Johnson et al., 2013). Thus, it may not be surprising that loss of several NPC components leads to DNA damage accumulation and hypersensitivity to DNA-damaging agents (Gao et al., 2011; Khadaroo et al., 2009; Lemaitre et al., 2012; Loeillet et al., 2005; Palancade et al., 2007). Additionally, WRN helicase defects in WS patients result in alterations in NPC and lamin B1 distributions (Li et al., 2013b). Although the NE-associated localization

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of DSBs in yeast is not observed in mammals, the question remains whether soluble NPC members are recruited together with DDR factors to DNA damage sites in the nuclear interior. Proteins are not the only macromolecules transported through the NPCs; after processing, the transcription-export (TREX) complex coordinates the nuclear export of mRNAs to the cytoplasm (Pena et al., 2012; Strasser et al., 2002). Interestingly, depletion of the TREX member THO in human cells results in R-loop-dependent genome instability and DSB accumulation (Dominguez-Sanchez et al., 2011; Hamperl and Cimprich, 2014). These findings as well as the diverse role of RNA-binding proteins involved in DNA repair (Kai, 2016; Savage et al., 2014; Wickramasinghe and Venkitaraman, 2016) highlighting the putative role of (non-) coding RNAs in DDR. Apart from the transcription- and sensor-related nuclear transport that serves as a link of DNA repair to the immune response, the NPCs also play a role in viral infection (Wirthmueller et al., 2013). Extensive studies show that viruses exploit the transport machinery of the host cell to enter or exit its nucleus, thereby evading immune activation (reviewed in Fulcher and Jans (2011), Randall and Goodbourn (2008), Yarbrough et al. (2014)). In support, viral infections are often associated with increased levels of ␥H2AX and activated ATM (Lilley et al., 2010, 2007) providing with a link to DDR induction; not surprisingly, some viruses are known to exploit or inactivate the DNA repair machinery to replicate their own genome (Kudoh et al., 2009; Lilley et al., 2011; Stracker et al., 2002). 7. Subnuclear compartments in DDR: the nucleolus Nucleoli represent perhaps the most prominent structures amongst nuclear compartments. They form around ribosomal gene arrays (rDNA) for rRNA synthesis, ribosome assembly and RNA processing (Olson et al., 2002). Although the nucleoli are known to include DNA repair factors, little is known about the functional links between DDR factors and the nucleolus (Larsen and Stucki, 2016; Grummt, 2013). Upon stress, a subset of nucleolar factors involved in cell cycle, apoptosis or DNA repair are relocalized to the nucleoplasm (Olson and Dundr, 2005; Boulon et al., 2010). Notably, some nucleolar effectors are also involved in DNA repair (Fig. 1D) (Boisvert and Lamond, 2010). For instance, nucleolin (NCL) plays a role in the fine-tuning of PCNA in NER pathway (Yang et al., 2009). Nucleophosmin (NPM) is linked to BER modulation (Poletto et al., 2014). Conversely, there are instances where DNA damageassociated proteins play a physiological role in nucleoli-associated processes other than DNA repair. For example, the WRN helicase and the flap endonuclease (FEN) 1 are required for ribosomal gene transcription (Shiratori et al., 2002; Guo et al., 2008). Moreover, the DNA repair AP-endonuclease (APE) 1 interacts with NPM and acts as an RNA damage sensor in nucleoli, where it cleaves aberrant RNA molecules; interestingly, upon DDR induction, both APE1 and NPM proteins translocate to the nucleoplasm (Antoniali et al., 2014; Vascotto et al., 2015). In turn, NPM may often act as an alarmin (endogenous DAMP) secreted by macrophages in response to lipopolysaccharide (LPS) stimulation triggering the release of pro-inflammatory cytokines (Fig. 1D) (Nawa et al., 2009). 8. Subnuclear compartments in DDR: PML bodies Promyelocytic leukemia protein (PML/TRIM 19) is a member of the tripartite motif (TRIM) family that forms high molecular weight protein complexes with characteristic subcellular structures. PML nuclear bodies (PML NBs) contain a large number of proteins whose function is linked to oncogenesis, DNA damageand stress-related responses, senescence as well as viral resistance (reviewed in Bernardi and Pandolfi (2007), Borden (2002), Dellaire and Bazett-Jones (2004)). The tumor-suppressive prop-

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erties of PML are mediated through diverse pathways leading to apoptosis or senescence (Wang et al., 1998). In agreement with the functional role of PMLs in DNA repair, PML NBs were recently shown to co-localize with the DNA damage marker ␥-H2AX (histone H2AX phosphorylated on serine 139), ATM upon ionizing radiation as well as with radiation-induced MRE11 foci (IRIF) and p53 at the late stages of DDR (Carbone et al., 2002). Upon exposure to genotoxic insults, PML NBs recruit Mdm2 (p53 E3 ubiquitin ligase) (Bernardi et al., 2004), the damage-induced kinase Chk2 (Yang et al., 2002), the deacetylase SIRT1 (Campagna et al., 2011; Cheng et al., 2003) and single-stranded DNA (Boe et al., 2006) and function as DNA damage sensors in an MRN-dependent manner (Fig. 1E) (Dellaire et al., 2006). Intriguingly, PML and the PML NB member SP100 increase rapidly in response to IFN treatment (Chelbi-Alix et al., 1995; Lavau et al., 1995) and their induction in macrophages and dendritic cells requires the IFN-regulatory factor 8 and p53 for antiviral defense (Dror et al., 2007). Besides the intrinsic role of PML-NBs in antiviral defense, evidence continues to accumulate on their emerging role in innate immune responses (Scherer and Stamminger, 2016).

9. Chromatin dynamics in DNA repair and the immune response Chromosomes are not randomly scattered in the nucleus. Instead, they are arranged in discrete regions, known as chromosome territories (CTs), which are radially localized from the center of the nucleus (Boyle et al., 2001; Cremer and Cremer, 2001). Although their position is tightly conserved through evolution, CTs do change during differentiation, senescence or disease or the neighboring nuclear architecture (Cremer and Cremer, 2001; Foster and Bridger, 2005; Ira and Hastings, 2012; Mehta et al., 2007). The radial distribution of chromosomes also correlates with transcription, as gene-poor chromosomes are mostly located at the nuclear periphery, while gene-rich chromosomes are essentially only present in the interior. As the nuclear periphery is associated with heterochromatin, the peripheral presence of genetic loci is mostly associated with transcriptional silencing; in support, several studies suggest higher transcriptional activity in the nuclear interior. Examples of such transcription-dependent reorganization of chromosomes originate from studies in T cell differentiation, where the CD4/CD8 lineage commitment dictates differential repositioning of the relevant loci and cytokine regulators (Hewitt et al., 2004; Kim et al., 2004). Intriguingly, the gene-rich chromatin that is found in the nuclear interior (gene-rich euchromatin) has higher GC content and is more prone to damage and faster DNA repair kinetics than the heterochromatic regions (Fig. 1F) (Gazave et al., 2005; Folle, 2008; Martinez-Lopez et al., 2001; Sanders et al., 2004). Such marked differences in DNA damage occurrence as well as repair kinetics likely represent the higher accessibility of low-compacted euchromatic regions to genotoxins or DNA repair factors. In line, depletion of HP1, or its interacting co-repressor KAP1, increases DNA repair efficiency (White et al., 2012) whereas overexpression of the nuclear oncogene SET results in KAP1-HP1 retention on chromatin and inhibits DNA-end resection and HR (Kalousi et al., 2015). Indeed, upon irradiation, HP1␤ and the nucleosome-binding protein HMGN1 dissociate from DNA damage sites, to facilitate proper DDR signaling (Ayoub et al., 2008; Birger et al., 2003; Kim et al., 2009). In agreement, heterochromatin is resistant to ␥-H2AX spreading from adjacent euchromatin (Kim et al., 2007). Taken together, the recent findings suggest that chromatin compaction, DDR signaling and DNA repair are highly interconnected and functionally linked within the nuclear microenvironment in a cell- and tissue-type dependent manner (Fig. 1F). Even more, since chromatin dynamics differ enormously between the different cell types.

Gene expression regulation is facilitated by genome-wide networks of chromosomal interactions between genes and regulatory elements located in distant sites within the compact nucleus (Miele and Dekker, 2008). Examples of such interactions include the two homologous X chromosomes during X chromosome inactivation (Anguera et al., 2006; Augui et al., 2007; Xu et al., 2006), imprinted loci (Ling et al., 2006; Zhang et al., 2014), as well as immunerelated genes (Deligianni and Spilianakis, 2012; Higgs and Wood, 2008; Palstra et al., 2008; Park et al., 2016; Spilianakis et al., 2005; Stratigi et al., 2015). Besides nuclear lamina-associated movement of damaged DNA, a lot of work has been done in yeast, mice and humans, to implicate DNA mobility with heterochromatin exclusion and repair efficiency (reviewed in (Dion and Gasser, 2013)). The homology search for efficient homologous recombination is also facilitated by such long-range movements (Dion et al., 2012; Mine-Hattab and Rothstein, 2012) that are frequently regulated by DNA damage checkpoint kinases and chromatin remodelers (reviewed in Dion and Gasser (2013)). Chromatin remodeling for chromatin decondensation and nucleosome repositioning, in relation to DNA repair and the DDR, has been studied extensively (Adam and Polo, 2014; Price and D’Andrea, 2013; Martínez-López et al., 2013). PARP-1 a chromatin remodeler that efficiently detects DNA damage and is involved DNA repair, provides an interesting link between chromatin organization, DNA repair and inflammation (Fig. 1G). In the absence of exogenous genotoxic insults, PARP-1 plays a role in the maintenance of nuclear organization through a cross-talk with the CCCTC-binding factor (CTCF), a chromatin organizer involved in epigenetic events and imprinting (Guastafierro et al., 2013; Zhao et al., 2015). It also participates in telomere maintenance, replicative stress resolution and cell cycle control. Besides, the functional role in genome stability and nuclear architecture, PARP-1 is known to regulate NF-␬B-dependent gene transcription and the stimulation of cytokine recruitment of immune cells. Specifically, it sustains the expression of cytokines like TNF␣, IL-1, IL-6, IFN␥, CCL3 and iNOS, increases the expression of cell adhesion molecules and chemoattractant cytokines and modulates the stimulation, differentiation and functionality of T and B cells (reviewed in Bai and Virag (2012), Rosado et al. (2013)). The multifunctionality of PARP1 is shared by other DNA repair factors. The NER factors have been shown to be recruited to active gene promoters, to be involved in chromatin remodeling and promote DNA accessibility (Kamileri et al., 2012; Le May et al., 2010). Furthermore, XPG and XPF are also known to recruit CTCF for chromatin looping and accurate gene expression (Klungland et al., 1999; Le May et al., 2012), while CSA is recruited to the nuclear matrix with relevance to the transcriptioncoupled repair of oxidative DNA damage (Kamiuchi et al., 2002). Moreover, BRCA1 involved in HR, also induces the expression of immune-related genes, like IRF-7, in cooperation with IFN␥, resulting in the stimulation of the innate immune response (Buckley et al., 2007). Thus, the ample involvement of DNA repair and DDR factors in nuclear organization and transcription offers a wide range of possibilities for the fine-tuning of DDR-induced inflammatory responses (Fig. 1G).

10. Concluding remarks DNA is vital for nearly all cellular processes and must be consequently repaired when damaged. To meet this challenge, mammalian cells have evolved genome maintenance and immune defense strategies that are closely coordinated and appropriately mobilized in a circumstantial and contextual manner. Indeed, rapid progress in the field has unveiled unprecedented functional links and parallels between immune DNA-sensing pathways and DDRmediated immune responses. DNA damage sensors are now known to trigger tissue-specific or systemic pro-inflammatory signals in

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response to both nuclear DNA damage and cytosolic DNA byproducts. At present, it remains unknown, how DNA repair factors and the DDR are functionally linked to innate immune signaling. Knowledge towards this direction is instrumental to specifically target e.g. senescent or cancer cells with increased DNA damage loads. Inseparably, nuclear architecture and chromatin organization provide an additional level of DDR regulation to be explored. Evidently, to account for the diversity of sensors and alterations in chromatin dynamics and subnuclear topology between different signaling pathways, cell types or tissues, much work needs to be done to dissect the mechanisms of DDR-induced inflammation in a contextual manner. The challenge remains to translate our knowledge into tangible benefits for the patients in the clinic, such as targeting chronically inflamed cells to battle age-related diseases, including cancer. Acknowledgements The FP7 Marie Curie ITN “Chromatin3D” (GA622934) and the Horizon 2020 ERC Consolidator grant “DeFiNER” (GA64663) supported this work. G.A.G was supported by the EMBO Young Investigator program. References Abraham, R.T., 2001. Cell cycle checkpoint signaling through the ATM and ATR kinases. Genes Dev. 15 (17), 2177–2196. Adam, S., Polo, S.E., 2014. Blurring the line between the DNA damage response and transcription: the importance of chromatin dynamics. Exp. Cell Res. 329 (1), 148–153. Anguera, M.C., et al., 2006. X-chromosome kiss and tell: how the Xs go their separate ways. Cold Spring Harb. Symp. Quant. Biol. 71, 429–437. Antoniali, G., et al., 2014. Emerging roles of the nucleolus in regulating the DNA damage response: the noncanonical DNA repair enzyme APE1/Ref-1 as a paradigmatical example. Antioxid. Redox Signal. 20 (4), 621–639. Aten, J.A., et al., 2004. Dynamics of DNA double-strand breaks revealed by clustering of damaged chromosome domains. Science 303 (5654), 92–95. Atianand, M.K., Fitzgerald, K.A., 2013. Molecular basis of DNA recognition in the immune system. J. Immunol. 190 (5), 1911–1918. Augui, S., et al., 2007. Sensing X chromosome pairs before X inactivation via a novel X-pairing region of the Xic. Science 318 (5856), 1632–1636. Ayoub, N., et al., 2008. HP1-beta mobilization promotes chromatin changes that initiate the DNA damage response. Nature 453 (7195), 682–686. Bai, P., Virag, L., 2012. Role of poly(ADP-ribose) polymerases in the regulation of inflammatory processes. FEBS Lett. 586 (21), 3771–3777. Barber, G.N., 2011. Cytoplasmic DNA innate immune pathways. Immunol. Rev. 243 (1), 99–108. Bernardi, R., Pandolfi, P.P., 2007. Structure, dynamics and functions of promyelocytic leukaemia nuclear bodies. Nat. Rev. Mol. Cell Biol. 8 (12), 1006–1016. Bernardi, R., et al., 2004. PML regulates p53 stability by sequestering Mdm2 to the nucleolus. Nat. Cell Biol. 6 (7), 665–672. Birger, Y., et al., 2003. Chromosomal protein HMGN1 enhances the rate of DNA repair in chromatin. EMBO J. 22 (7), 1665–1675. Boe, S.O., et al., 2006. Promyelocytic leukemia nuclear bodies are predetermined processing sites for damaged DNA. J. Cell Sci. 119 (Pt. 16), 3284–3295. Boisvert, F.M., Lamond, A.I., 2010. p53-Dependent subcellular proteome localization following DNA damage. Proteomics 10 (22), 4087–4097. Borden, K.L., 2002. Pondering the promyelocytic leukemia protein (PML) puzzle: possible functions for PML nuclear bodies. Mol. Cell. Biol. 22 (15), 5259–5269. Boulon, S., et al., 2010. The nucleolus under stress. Mol. Cell 40 (2), 216–227. Boyle, S., et al., 2001. The spatial organization of human chromosomes within the nuclei of normal and emerin-mutant cells. Hum. Mol. Genet. 10 (3), 211–219. Brooks, P.J., Cheng, T.F., Cooper, L., 2008. Do all of the neurologic diseases in patients with DNA repair gene mutations result from the accumulation of DNA damage? DNA Repair (Amst.) 7 (6), 834–848. Brzostek-Racine, S., et al., 2011. The DNA damage response induces IFN. J. Immunol. 187 (10), 5336–5345. Buckley, N.E., et al., 2007. BRCA1 regulates IFN-gamma signaling through a mechanism involving the type I IFNs. Mol. Cancer Res. 5 (3), 261–270. Burdette, D.L., et al., 2011. STING is a direct innate immune sensor of cyclic di-GMP. Nature 478 (7370), 515–518. Butin-Israeli, V., Adam, S.A., Goldman, R.D., 2013. Regulation of nucleotide excision repair by nuclear lamin b1. PLoS One 8 (7), e69169. Butin-Israeli, V., et al., 2015. Role of lamin b1 in chromatin instability. Mol. Cell. Biol. 35 (5), 884–898. Campagna, M., et al., 2011. SIRT1 stabilizes PML promoting its sumoylation. Cell Death Differ. 18 (1), 72–79.

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