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RNA-directed repair of DNA double-strand breaks
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RNA-directed repair of DNA double-strand breaks Yun-Gui Yang a,b,∗ , Yijun Qi c,d,∗ a
Key Laboratory of Genomics and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China University of Chinese Academy of Sciences, Beijing 100049, China c Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China d Center for Plant Biology, School of Life Sciences, Tsinghua University, Beijing 100084, China b
a r t i c l e
i n f o
Article history: Available online xxx Keywords: DNA damage response DNA repair RNA MicroRNA diRNA Double-strand break
a b s t r a c t DNA double-strand breaks (DSBs) are among the most deleterious DNA lesions, which if unrepaired or repaired incorrectly can cause cell death or genome instability that may lead to cancer. To counteract these adverse consequences, eukaryotes have evolved a highly orchestrated mechanism to repair DSBs, namely DNA-damage-response (DDR). DDR, as defined specifically in relation to DSBs, consists of multilayered regulatory modes including DNA damage sensors, transducers and effectors, through which DSBs are sensed and then repaired via DNAprotein interactions. Unexpectedly, recent studies have revealed a direct role of RNA in the repair of DSBs, including DSB-induced small RNA (diRNA)-directed and RNAtemplated DNA repair. Here, we summarize the recent discoveries of RNA-mediated regulation of DSB repair and discuss the potential impact of these novel RNA components of the DSB repair pathway on genomic stability and plasticity. © 2015 Elsevier B.V. All rights reserved.
1. Introduction Eukaryotic DNA sustains constant threats from deleterious endogenous and environmental agents. Double-strand DNA breaks (DSBs) are arguably the most toxic DNA lesions [1]. If left unrepaired, one lesion can induce cell death or oncogenic chromosomal translocations. Cells have evolved a highly conserved and orchestrated DNA damage response (DDR) network to sense DSBs and mediate repair [1,2]. There are prominent, conserved DSB repair mechanisms: error-prone non-homologous end-joining (NHEJ), faithful homologous recombination (HR), alternative NHEJ and single strand annealing [3]. Dynamic spatial, physical and temporal organizational properties of the protein-based multiple regulatory layers of DSB repair have been reviewed in detail elsewhere [1,4–9]. Interestingly besides the involvement of proteins, efficient DSB repair also requires RNA elements including microRNAs, diRNAs and template RNA [10–14]. In this review, we focus upon recent dis-
Abbreviations: DSBs, DNA double-strand breaks; DDR, DNA-damage-response as defined specifically in relation to DSBs; diRNA, DSB-induced small RNA; NHEJ, non-homologous end-joining; HR, homologous recombination; Ago2, Argonaute2; RISC, RNA-induced silencing complex. ∗ Corresponding authors at: Key Laboratory of Genomics and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China and Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China. E-mail addresses: [email protected] (Y.-G. Yang), [email protected] (Y. Qi).
coveries of RNA-based regulatory layers of DSB repair and discuss their potential impacts on genome stability. 2. MicroRNAs regulate DNA repair genes MicroRNAs (miRNAs) are a family of small non-coding RNAs that destabilize and repress translation of their target messenger RNAs. MiRNAs play an important regulatory role in various biological processes. Emerging evidence indicates that miRNAs can regulate the expression of central components of the DDR machinery, which may have a role in feedback regulation of miRNA expression. There are excellent reviews about modulation of miRNA expression during DDR [15–17]. Here, we summarize recent studies on the functions of miRNAs in the DDR to DSBs. MiRNAs have been shown to target cell cycle checkpoint genes, thereby influencing DNA damage repair. Multiple DNA damage agents can induce the expression of several miRNA families including miR-15a/b, miR-16, miR-21, miR-34, let-7 and miR-24 [18–23]. miR-21 and miR-16 repress the expression of critical cell cycle checkpoint phosphatases CDC25A and WIP1 and then modulate cell cycle checkpoint activation [19,24–26]. The p53-dependent miR-34 can regulate G1/S and S-phase checkpoints by modulating multiple genes including E2F, cyclinE2, CDK4/CDK6, and c-MYC [27–31]. let-7 regulates G1/S and G2/M cell cycle checkpoints by targeting E2F2, cyclin D2, Cdc34/cyclins D1/D3/A and Cdk4, respectively [23,32–34], while miR-24 activates the G1/S cell cycle checkpoint mainly by targeting E2F2 [35]. DNA damage can also down-regulate the expression of some miRNA families including miR-106b, miR-
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Fig. 1. Working model for RNA-directed repair of DSBs. MicroRNAs regulate DNA damage repair genes as indicated. DiRNAs regulate the recruitment of Ago2–Rad51 complexes to DSB site through base pairing between diRNAs and homologous DNA sequences surrounding the break site or scaffold RNA transcripts (red dashed line) generated from around the break site. Rad52-dependent template-RNAs direct DNA repair as indicated (template-RNAs as red solid line). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
17 miR-421, miR-101 and miR-100, which then activate cell cycle checkpoint [36–39]. The down-regulation of miR-106b regulates p21-dependent G2/M cell cycle arrest [40]. miR-17-92, miR-106a and miR-106b-25 actively participate in cell cycle control by targeting E2F1-associated G1 checkpoint activation [41–43]. miR-17-5p targets specific genes required for the G1/S transition [44]. These findings suggest that miRNAs have complex roles in targeting either negative or positive regulators of the cell cycle checkpoint upon DDR. miRNAs can also target DNA repair or damage response genes and modulate levels of DNA repair proteins. Several miRNAs including miR-421, miR-101 and miR-100 repress ATM expression [45–47]. miR-101 also targets DNA-PKcs miR-124 regulates Ku70 expression [48,49], and miR-138 and miR-24 both targets histone H2AX [50,51]. miR-182 suppresses BRCA1, whereas miR96 represses RAD51 and REV1 [52–54]. Expression of these miRNAs turns out to be down-regulated in response to DNA damage. Therefore, down-regulation of these miRNAs may release their inhibitory effects and allow DNA repair proteins to rapidly accumulate upon DNA damage. In contrast to the above down-regulated miRNAs, some miRNAs targeting DNA repair or DDR genes are up-regulated upon DNA damage. These include miR-146a and miR-146b-5p that targets BRCA1 [55] and miR-155 that targets mismatch repair genes MLH1 and MSH2 [56,57]. These miRNAs may be required for appropriate activation of DDR and DSB repair. Collectively, miRNAs provide a new regulatory layer of DDR and DSB repair genes at the post-transcriptional level (Fig. 1). Detailed mechanisms underlying their cooperative roles will require further investigation. 3. DiRNAs recruit DNA repair factors Recent studies have shown that a new class of 21 nt-long small RNAs can be induced by DSBs from the sequences in vicinity of DSB sites in several species [58–60]. The generation of these small RNAs (namely DSB-induced small RNAs, or diRNAs) is Dicer-dependent. diRNAs are bound by Argonaute2 (Ago2), the core component of
RNA-induced silencing complex (RISC) in RNAi. Consistently, depletion of Dicer or Ago2 but not other Agos decreases HR repair efficiency of DSBs [61]. Several possible mechanisms through which diRNA mediates DSB repair can be envisioned: (1) Ago2–diRNA may modulate the activity of DNA damage response kinases, including ATM and ATR, and then influence DSB lesion sensing; (2) Ago2–diRNA may regulate cell-cycle progression and affect the expression of DNA repair proteins; (3) Ago2–diRNA may recruit chromatin modifying complexes to alter chromatin status, which in turn regulates the access and/or dissociation of repair factors to/from chromatin near DSBs; (4) Ago2–diRNA may guide repair factors to DSB sites to facilitate repair; (5) Ago2–diRNA may function in Rad51-mediated homology search or at a later stage of HR. Depletion of Dicer or Ago2 did not alter cell cycle distributions and major histone modifications (our unpublished observations), suggesting that diRNAs are unlikely involved in regulating cell cycle progression and chromatin modification. Moreover, indirect fluorescence and Western-blotting approaches revealed that both phosphorylation of ATM/ATR and their targets Chk2, Chk1 and RPA, as well as focus formation of MDC1 and 53BP1 appeared to have no significant changes in Dicer- and Ago2-deficient cells [61], excluding potential participation of diRNAs in ATM-mediated DNA damage sensing. Rad51 forms repair foci at DSB sites upon DNA damage and plays a critical role in the exchange of single-strand DNAs during HR repair of DSBs [61]. Intriguingly, Ago2 interacted with Rad51 and such interaction was enhanced following ionizing-radiation (IR). This raised a possibility that Ago2–diRNA may regulate Rad51 focus formation. Indeed, the recruitment of Rad51 but not other DDR proteins including ␥-H2AX, RPA, 53BP1 and MDC1, was severely compromised at IR-induced DSB sites in Dicer- or Ago2 or Dicer-depleted cells. In addition, mutant Ago2 proteins that are deficient in either small RNA binding or Slicer activity could neither retain the recruitment of Rad51 to DSB sites nor restore HR repair in Ago2-deficient cells, albeit they were still able to interact with Rad51 [61]. Based on current data, it is appealing to propose that the Ago2/diRNA complex recruits Rad51 and then targets it onto DSBs
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through base pairing between diRNAs and DNA sequences adjacent to the break sites and/or RNA transcripts transcribed from DNA sequences around the break sites (Fig. 1) [10,11,14].
Conflict of interest
4. Template-RNAs direct DNA repair
Acknowledgments
Several artificial RNA elements have been shown to function as direct templates for DSB repair in eukaryotic cells (13, 62, 63). This challenges the conventional wisdom that HR strand exchange occurs only between two DNA molecules. Artificial RNA species including synthetic RNAs and long RNA templates can guide genomic rearrangements [13,62]. Similar to RNA-mediated HR between molecules in RNA viruses, Storici and co-workers recently demonstrated that endogenous transcript RNA can also promote HR at DSB sites in yeast Saccharomyces cerevisiae chromosome [13,62], suggesting the generality of reversible genetic information transfer from RNA to DNA in eukaryotes. A robust genetic reporter system has been developed to directly detect HR events initiated by transcript RNA in reverse-transcription-defective yeast strains [63]. The RNA transcript templates can accomplish repair of chromosomal DSBs depending on homologous sequences instead of chromosomal loci. This type of RNA–DNA recombination is prevented by Ribonucleases H1 and H2. DSB repair prefers the classic complementary DNA intermediate pathway in H-type ribonucleases proficient cells, but it favors RNA–DNA recombination in cells defective in those ribonucleases. At the molecular level, Rad52 seems to antagonize the inhibitory effects of ribonucleases and is required for efficiently annealing of RNA to a DSB-like DNA end at least in vitro [63]. RNA-templated DSB repair brings a brand new HR repair mechanism in eukaryotic cells (Fig. 1). Given that RNA transcripts are abundant nucleic acids in living organisms, their generality and plasticity in DSB repair and impact on genome integrity warrant further detailed investigation.
We thank MM Liu and Y Li for their scientific inputs. This work was supported by 973 programs 2011CB510103, 2012CB910900, NSFC grants 31370796, 31430022, 31225015, CAS Strategic Priority Research Program XDB14030300. We apologize for not being able to cite all the publications related to this topic due to space constraints.
5. Perspectives Given the importance of DNA damage repair for the maintenance of genome integrity and the survival of a cell, cells have evolved complex repair machinery that are thought to be build up solely by proteins. Recent discoveries have revealed that RNAs including small non-coding RNAs (miRNAs and diRNAs) and template RNAs can serves as novel regulatory components in the DSB repair pathway. It will be very exciting to have future studies dissecting the molecular and biochemical underpinnings of these RNAs in DSB repair. In addition to further exploring the functions and mechanisms of the above-mentioned RNA species in regulating DSB repair, it will be most exciting to identify novel regulatory RNA elements. Long non-coding RNAs (lncRNAs) are among the most promising targets. lncRNAs are classified as RNA transcripts that are longer than 200 nt and do not have coding potential. Nearly 15,000 unique lncRNAs are predicted by the GENCODE in humans [64,65]. Accumulating evidence has reveal that lncRNAs play critical roles in various biological processes [66–69]. The rich information stored in the primary sequences and secondary/tertiary structures of lncRNAs makes them well suited to function as scaffolds for molecular interaction [64,70]. Given that DNA damage repair involves complex protein–protein and protein–DNA interactions, it will be of great interest to investigate whether lncRNAs are involved in these interactions and serve as scaffolds for the assembly of DNA repair machinery during DNA repair process. Identification of this multilayered RNA regulation of DNA damage repair will deepen our understanding how DNA repair machinery efficiently and accurately maintains genome stability.
The authors declare that they have no conflict of interest.
References [1] T. Iyama, D.M. Wilson 3rd, DNA repair mechanisms in dividing and non-dividing cells, DNA Repair (Amst.) 12 (8) (2013) 620–636. [2] J.N. Kavanagh, et al., DNA double strand break repair: a radiation perspective, Antioxid. Redox Signal. 18 (18) (2013) 2458–2472. [3] S.C. West, et al., Double-strand break repair in human cells, Cold Spring Harb. Symp. Quant. Biol. 65 (2000) 315–321. [4] V. Dion, S.M. Gasser, Chromatin movement in the maintenance of genome stability, Cell 152 (6) (2013) 1355–1364. [5] Y. Doksani, T. de Lange, The role of double-strand break repair pathways at functional and dysfunctional telomeres, Cold Spring Harb. Perspect. Biol. 6 (12) (2014). [6] F. Gong, K.M. Miller, Mammalian DNA repair: HATs and HDACs make their mark through histone acetylation, Mutat. Res. 750 (1–2) (2013) 23–30. [7] A.A. Goodarzi, P.A. Jeggo, The repair and signaling responses to DNA double-strand breaks, Adv. Genet. 82 (2013) 1–45. [8] B.D. Price, A.D. D’Andrea, Chromatin remodeling at DNA double-strand breaks, Cell 152 (6) (2013) 1344–1354. [9] J. Vignard, G. Mirey, B. Salles, Ionizing-radiation induced DNA double-strand breaks: a direct and indirect lighting up, Radiother. Oncol. 108 (3) (2013) 362–369. [10] F. d’Adda di Fagagna, A direct role for small non-coding RNAs in DNA damage response, Trends Cell Biol. 24 (3) (2014) 171–178. [11] Z. Ba, Y. Qi, Small RNAs: emerging key players in DNA double-strand break repair, Sci. China Life Sci. 56 (10) (2013) 933–936. [12] G. Wan, et al., miRNA response to DNA damage, Trends Biochem. Sci. 36 (9) (2011) 478–484. [13] H. Keskin, et al., Transcript-RNA-templated DNA. recombination and repair, Nature 515 (7527) (2014) 436–439. [14] S. Yamanaka, H. Siomi, diRNA-Ago2-RAD51 complexes at double-strand break sites, Cell Res. 24 (5) (2014) 511–512. [15] G. Bottai, et al., Targeting the microRNA-regulating DNA damage/repair pathways in cancer, Expert Opin. Biol. Ther. 14 (11) (2014) 1667–1683. [16] M. Garofalo, C.M. Croce, MicroRNAs as therapeutic targets in chemoresistance, Drug Resist. Updates 16 (3–5) (2013) 47–59. [17] C. Han, et al., Crosstalk between the DNA damage response pathway and microRNAs, Cell Mol. Life Sci. 69 (17) (2012) 2895–2906. [18] M. Ofir, D. Hacohen, D. Ginsberg, MiR-15 and miR-16 are direct transcriptional targets of E2F1 that limit E2F-induced proliferation by targeting cyclin E, Mol. Cancer Res. 9 (4) (2011) 440–447. [19] P. Wang, et al., microRNA-21 negatively regulates Cdc25A and cell cycle progression in colon cancer cells, Cancer Res. 69 (20) (2009) 8157–8165. [20] M. Liu, et al., Regulation of the cell cycle gene: BTG2, by miR-21 in human laryngeal carcinoma, Cell Res. 19 (7) (2009) 828–837. [21] D.G. Zhang, J.N. Zheng, D.S. Pei, P53/microRNA-34-induced metabolic regulation: new opportunities in anticancer therapy, Mol. Cancer 13 (2014) 115. [22] J.Y. Zhou, et al., Analysis of microRNA expression profiles during the cell cycle in synchronized HeLa cells, BMB Rep. 42 (9) (2009) 593–598. [23] X. Sun, et al., Let-7: a regulator of the ERalpha signaling pathway in human breast tumors and breast cancer stem cells, Oncol. Rep. 29 (5) (2013) 2079–2087. [24] P.E. de Oliveira, et al., Hypoxia-mediated regulation of Cdc25A phosphatase by p21 and miR-21, Cell Cycle 8 (19) (2009) 3157–3164. [25] M. Rahman, et al., miR-15b/16-2 regulates factors that promote p53 phosphorylation and augments the DNA damage response following radiation in the lung, J. Biol. Chem. 289 (38) (2014) 26406–26416. [26] X. Zhang, et al., Oncogenic Wip1 phosphatase is inhibited by miR-16 in the DNA damage signaling pathway, Cancer Res. 70 (18) (2010) 7176–7186. [27] L. Boominathan, The guardians of the genome (p53: TA-p73, and TA-p63) are regulators of tumor suppressor miRNAs network, Cancer Metastasis Rev. 29 (4) (2010) 613–639. [28] Y.H. Cha, et al., MiRNA-34 intrinsically links p53 tumor suppressor and Wnt signaling, Cell Cycle 11 (7) (2012) 1273–1281. [29] T.C. Chang, et al., Transactivation of miR-34a by p53 broadly influences gene expression and promotes apoptosis, Mol. Cell 26 (5) (2007) 745–752.
Please cite this article in press as: Y.-G. Yang, Y. Qi, RNA-directed repair of DNA double-strand breaks, DNA Repair (2015), http://dx.doi.org/10.1016/j.dnarep.2015.04.017
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ARTICLE IN PRESS Y.-G. Yang, Y. Qi / DNA Repair xxx (2015) xxx–xxx
[30] L. He, et al., A microRNA component of the p53 tumour suppressor network, Nature 447 (7148) (2007) 1130–1134. [31] N.H. Kim, et al., p53 regulates nuclear GSK-3 levels through miR-34-mediated Axin2 suppression in colorectal cancer cells, Cell Cycle 12 (10) (2013) 1578–1587. [32] H. Tang, et al., Let-7g microRNA sensitizes fluorouracil-resistant human hepatoma cells, Pharmazie 69 (4) (2014) 287–292. [33] A. Tzatsos, et al., Lysine-specific demethylase 2B (KDM2B)-let-7-enhancer of zester homolog 2 (EZH2) pathway regulates cell cycle progression and senescence in primary cells, J. Biol. Chem. 286 (38) (2011) 33061–33069. [34] C.D. Johnson, et al., The let-7 microRNA represses cell proliferation pathways in human cells, Cancer Res. 67 (16) (2007) 7713–7722. [35] A. Lal, et al., miR-24 Inhibits cell proliferation by targeting E2F2: MYC, and other cell-cycle genes via binding to seedless 3’UTR microRNA recognition elements, Mol. Cell 35 (5) (2009) 610–625. [36] S. Gupta, et al., Perk-dependent repression of miR-106b-25 cluster is required for ER stress-induced apoptosis, Cell Death Dis. 3 (2012) pe333. [37] M. Hackl, et al., miR-17: miR-19b, miR-20a, and miR-106a are down-regulated in human aging, Aging Cell 9 (2) (2010) 291–296. [38] P. Dmitriev, et al., Defective regulation of microRNA target genes in myoblasts from facioscapulohumeral dystrophy patients, J. Biol. Chem. 288 (49) (2013) 34989–35002. [39] A.C. Mueller, D. Sun, A. Dutta, The miR-99 family regulates the DNA damage response through its target SNF2H, Oncogene 32 (9) (2013) 1164–1172. [40] I. Ivanovska, et al., MicroRNAs in the miR-106b family regulate p21/CDKN1A and promote cell cycle progression, Mol. Cell Biol. 28 (7) (2008) 2167–2174. [41] H.I. Trompeter, et al., MicroRNAs MiR-17, MiR-20a, and MiR-106b act in concert to modulate E2F activity on cell cycle arrest during neuronal lineage differentiation of USSC, PLoS One 6 (1) (2011) e16138. [42] G. Yang, et al., MiR-106a inhibits glioma cell growth by targeting E2F1 independent of p53 status, J. Mol. Med. (Berl.) 89 (10) (2011) 1037–1050. [43] S. He, et al., Aurora kinase A induces miR-17-92 cluster through regulation of E2F1 transcription factor, Cell Mol. Life Sci. 67 (12) (2010) 2069–2076. [44] N. Cloonan, et al., The miR-17-5p microRNA is a key regulator of the G1/S phase cell cycle transition, Genome Biol. 9 (8) (2008) R127. [45] A. Di Francesco, et al., The DNA-damage response to gamma-radiation is affected by miR-27a in A549 cells, Int. J. Mol. Sci. 14 (9) (2013) 17881–17896. [46] N.T. Martin, et al., ATM-dependent MiR-335 targets CtIP and modulates the DNA damage response, PLoS Genet. 9 (5) (2013) e1003505. [47] D. Yan, et al., Targeting DNA-PKcs and ATM with miR-101 sensitizes tumors to radiation, PLoS One 5 (7) (2010) e11397. [48] F. Zhu, et al., MicroRNA-124 (miR-124) regulates Ku70 expression and is correlated with neuronal death induced by ischemia/reperfusion, J. Mol. Neurosci. 52 (1) (2014) 148–155. [49] S. Chen, et al., Radiosensitizing effects of ectopic miR-101 on non-small-cell lung cancer cells depend on the endogenous miR-101 level, Int. J. Radiat. Oncol. Biol. Phys. 81 (5) (2011) 1524–1529.
[50] Y. Wang, et al., MicroRNA-138 modulates DNA damage response by repressing histone H2AX expression, Mol. Cancer Res. 9 (8) (2011) 1100–1111. [51] A. Lal, et al., miR-24-mediated downregulation of H2AX suppresses DNA repair in terminally differentiated blood cells, Nat. Struct. Mol. Biol. 16 (5) (2009) 492–498. [52] K. Krishnan, et al., MicroRNA-182-5p targets a network of genes involved in DNA repair, RNA 19 (2) (2013) 230–242. [53] P. Moskwa, et al., miR-182-mediated downregulation of BRCA1 impacts DNA repair and sensitivity to PARP inhibitors, Mol. Cell 41 (2) (2011) 210–220. [54] Y. Wang, et al., MiR-96 downregulates REV1 and RAD51 to promote cellular sensitivity to cisplatin and PARP inhibition, Cancer Res. 72 (16) (2012) 4037–4046. [55] J. Shen, et al., A functional polymorphism in the miR-146a gene and age of familial breast/ovarian cancer diagnosis, Carcinogenesis 29 (10) (2008) 1963–1966. [56] W.J. Liu, et al., MLH1 as a direct target of MiR-155 and a potential predictor of favorable prognosis in pancreatic cancer, J. Gastrointest. Surg. 17 (8) (2013) 1399–1405. [57] N. Valeri, et al., Modulation of mismatch repair and genomic stability by miR-155, Proc. Natl. Acad. Sci. U. S. A. 107 (15) (2010) 6982–6987. (15) (2010) 6982–6987. [58] W. Wei, et al., A role for small RNAs in DNA double-strand break repair, Cell 149 (1) (2012) 101–112. [59] S. Francia, et al., Site-specific DICER and DROSHA RNA. products control the DNA-damage response, Nature 488 (7410) (2012) 231–235. [60] K.M. Michalik, R. Bottcher, K. Forstemann, A small RNA response at DNA ends in Drosophila, Nucleic Acids Res. 40 (19) (2012) 9596–9603. [61] M. Gao, et al., Ago2 facilitates Rad51 recruitment and DNA double-strand break repair by homologous recombination, Cell Res. 24 (5) (2014) 532–541. [62] F. Storici, et al., RNA-templated DNA repair, Nature 447 (7142) (2007) 338–341. [63] H. Keskin, et al., Transcript-RNA-templated DNA recombination and repair, Nature 515 (7527) (2014) 436–439. [64] T. Derrien, et al., The GENCODE v7 catalog of human long noncoding RNAs: analysis of their gene structure, evolution, and expression, Genome Res. 22 (9) (2012) 1775–1789. [65] J. Harrow, et al., GENCODE: the reference human genome annotation for The ENCODE Project, Genome Res. 22 (9) (2012) 1760–1774. [66] M. Kataoka, D.Z. Wang, Non-coding RNAs including miRNAs and lncRNAs in cardiovascular biology and disease, Cells 3 (3) (2014) 883–898. [67] M.N. Rossi, F. Antonangeli, LncRNAs: new players in apoptosis control, Int. J. Cell Biol. 2014 (2014) 473857. [68] J. Zhu, et al., Function of lncRNAs and approaches to lncRNA-protein interactions, Sci. China Life Sci. 56 (10) (2013) 876–885. [69] P.M. Guenzl, D.P. Barlow, Macro lncRNAs: a new layer of cis-regulatory information in the mammalian genome, RNA Biol. 9 (6) (2012) 731–741. [70] I.V. Novikova, et al., Rise of the RNA machines: exploring the structure of long non-coding RNAs, J. Mol. Biol. 425 (19) (2013) 3731–3746.
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RNA-directed repair of DNA double-strand breaks Yun-Gui Yang a,b,∗ , Yijun Qi c,d,∗ a
Key Laboratory of Genomics and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China University of Chinese Academy of Sciences, Beijing 100049, China c Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China d Center for Plant Biology, School of Life Sciences, Tsinghua University, Beijing 100084, China b
a r t i c l e
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Article history: Available online xxx Keywords: DNA damage response DNA repair RNA MicroRNA diRNA Double-strand break
a b s t r a c t DNA double-strand breaks (DSBs) are among the most deleterious DNA lesions, which if unrepaired or repaired incorrectly can cause cell death or genome instability that may lead to cancer. To counteract these adverse consequences, eukaryotes have evolved a highly orchestrated mechanism to repair DSBs, namely DNA-damage-response (DDR). DDR, as defined specifically in relation to DSBs, consists of multilayered regulatory modes including DNA damage sensors, transducers and effectors, through which DSBs are sensed and then repaired via DNAprotein interactions. Unexpectedly, recent studies have revealed a direct role of RNA in the repair of DSBs, including DSB-induced small RNA (diRNA)-directed and RNAtemplated DNA repair. Here, we summarize the recent discoveries of RNA-mediated regulation of DSB repair and discuss the potential impact of these novel RNA components of the DSB repair pathway on genomic stability and plasticity. © 2015 Elsevier B.V. All rights reserved.
1. Introduction Eukaryotic DNA sustains constant threats from deleterious endogenous and environmental agents. Double-strand DNA breaks (DSBs) are arguably the most toxic DNA lesions [1]. If left unrepaired, one lesion can induce cell death or oncogenic chromosomal translocations. Cells have evolved a highly conserved and orchestrated DNA damage response (DDR) network to sense DSBs and mediate repair [1,2]. There are prominent, conserved DSB repair mechanisms: error-prone non-homologous end-joining (NHEJ), faithful homologous recombination (HR), alternative NHEJ and single strand annealing [3]. Dynamic spatial, physical and temporal organizational properties of the protein-based multiple regulatory layers of DSB repair have been reviewed in detail elsewhere [1,4–9]. Interestingly besides the involvement of proteins, efficient DSB repair also requires RNA elements including microRNAs, diRNAs and template RNA [10–14]. In this review, we focus upon recent dis-
Abbreviations: DSBs, DNA double-strand breaks; DDR, DNA-damage-response as defined specifically in relation to DSBs; diRNA, DSB-induced small RNA; NHEJ, non-homologous end-joining; HR, homologous recombination; Ago2, Argonaute2; RISC, RNA-induced silencing complex. ∗ Corresponding authors at: Key Laboratory of Genomics and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China and Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China. E-mail addresses: [email protected] (Y.-G. Yang), [email protected] (Y. Qi).
coveries of RNA-based regulatory layers of DSB repair and discuss their potential impacts on genome stability. 2. MicroRNAs regulate DNA repair genes MicroRNAs (miRNAs) are a family of small non-coding RNAs that destabilize and repress translation of their target messenger RNAs. MiRNAs play an important regulatory role in various biological processes. Emerging evidence indicates that miRNAs can regulate the expression of central components of the DDR machinery, which may have a role in feedback regulation of miRNA expression. There are excellent reviews about modulation of miRNA expression during DDR [15–17]. Here, we summarize recent studies on the functions of miRNAs in the DDR to DSBs. MiRNAs have been shown to target cell cycle checkpoint genes, thereby influencing DNA damage repair. Multiple DNA damage agents can induce the expression of several miRNA families including miR-15a/b, miR-16, miR-21, miR-34, let-7 and miR-24 [18–23]. miR-21 and miR-16 repress the expression of critical cell cycle checkpoint phosphatases CDC25A and WIP1 and then modulate cell cycle checkpoint activation [19,24–26]. The p53-dependent miR-34 can regulate G1/S and S-phase checkpoints by modulating multiple genes including E2F, cyclinE2, CDK4/CDK6, and c-MYC [27–31]. let-7 regulates G1/S and G2/M cell cycle checkpoints by targeting E2F2, cyclin D2, Cdc34/cyclins D1/D3/A and Cdk4, respectively [23,32–34], while miR-24 activates the G1/S cell cycle checkpoint mainly by targeting E2F2 [35]. DNA damage can also down-regulate the expression of some miRNA families including miR-106b, miR-
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Fig. 1. Working model for RNA-directed repair of DSBs. MicroRNAs regulate DNA damage repair genes as indicated. DiRNAs regulate the recruitment of Ago2–Rad51 complexes to DSB site through base pairing between diRNAs and homologous DNA sequences surrounding the break site or scaffold RNA transcripts (red dashed line) generated from around the break site. Rad52-dependent template-RNAs direct DNA repair as indicated (template-RNAs as red solid line). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
17 miR-421, miR-101 and miR-100, which then activate cell cycle checkpoint [36–39]. The down-regulation of miR-106b regulates p21-dependent G2/M cell cycle arrest [40]. miR-17-92, miR-106a and miR-106b-25 actively participate in cell cycle control by targeting E2F1-associated G1 checkpoint activation [41–43]. miR-17-5p targets specific genes required for the G1/S transition [44]. These findings suggest that miRNAs have complex roles in targeting either negative or positive regulators of the cell cycle checkpoint upon DDR. miRNAs can also target DNA repair or damage response genes and modulate levels of DNA repair proteins. Several miRNAs including miR-421, miR-101 and miR-100 repress ATM expression [45–47]. miR-101 also targets DNA-PKcs miR-124 regulates Ku70 expression [48,49], and miR-138 and miR-24 both targets histone H2AX [50,51]. miR-182 suppresses BRCA1, whereas miR96 represses RAD51 and REV1 [52–54]. Expression of these miRNAs turns out to be down-regulated in response to DNA damage. Therefore, down-regulation of these miRNAs may release their inhibitory effects and allow DNA repair proteins to rapidly accumulate upon DNA damage. In contrast to the above down-regulated miRNAs, some miRNAs targeting DNA repair or DDR genes are up-regulated upon DNA damage. These include miR-146a and miR-146b-5p that targets BRCA1 [55] and miR-155 that targets mismatch repair genes MLH1 and MSH2 [56,57]. These miRNAs may be required for appropriate activation of DDR and DSB repair. Collectively, miRNAs provide a new regulatory layer of DDR and DSB repair genes at the post-transcriptional level (Fig. 1). Detailed mechanisms underlying their cooperative roles will require further investigation. 3. DiRNAs recruit DNA repair factors Recent studies have shown that a new class of 21 nt-long small RNAs can be induced by DSBs from the sequences in vicinity of DSB sites in several species [58–60]. The generation of these small RNAs (namely DSB-induced small RNAs, or diRNAs) is Dicer-dependent. diRNAs are bound by Argonaute2 (Ago2), the core component of
RNA-induced silencing complex (RISC) in RNAi. Consistently, depletion of Dicer or Ago2 but not other Agos decreases HR repair efficiency of DSBs [61]. Several possible mechanisms through which diRNA mediates DSB repair can be envisioned: (1) Ago2–diRNA may modulate the activity of DNA damage response kinases, including ATM and ATR, and then influence DSB lesion sensing; (2) Ago2–diRNA may regulate cell-cycle progression and affect the expression of DNA repair proteins; (3) Ago2–diRNA may recruit chromatin modifying complexes to alter chromatin status, which in turn regulates the access and/or dissociation of repair factors to/from chromatin near DSBs; (4) Ago2–diRNA may guide repair factors to DSB sites to facilitate repair; (5) Ago2–diRNA may function in Rad51-mediated homology search or at a later stage of HR. Depletion of Dicer or Ago2 did not alter cell cycle distributions and major histone modifications (our unpublished observations), suggesting that diRNAs are unlikely involved in regulating cell cycle progression and chromatin modification. Moreover, indirect fluorescence and Western-blotting approaches revealed that both phosphorylation of ATM/ATR and their targets Chk2, Chk1 and RPA, as well as focus formation of MDC1 and 53BP1 appeared to have no significant changes in Dicer- and Ago2-deficient cells [61], excluding potential participation of diRNAs in ATM-mediated DNA damage sensing. Rad51 forms repair foci at DSB sites upon DNA damage and plays a critical role in the exchange of single-strand DNAs during HR repair of DSBs [61]. Intriguingly, Ago2 interacted with Rad51 and such interaction was enhanced following ionizing-radiation (IR). This raised a possibility that Ago2–diRNA may regulate Rad51 focus formation. Indeed, the recruitment of Rad51 but not other DDR proteins including ␥-H2AX, RPA, 53BP1 and MDC1, was severely compromised at IR-induced DSB sites in Dicer- or Ago2 or Dicer-depleted cells. In addition, mutant Ago2 proteins that are deficient in either small RNA binding or Slicer activity could neither retain the recruitment of Rad51 to DSB sites nor restore HR repair in Ago2-deficient cells, albeit they were still able to interact with Rad51 [61]. Based on current data, it is appealing to propose that the Ago2/diRNA complex recruits Rad51 and then targets it onto DSBs
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through base pairing between diRNAs and DNA sequences adjacent to the break sites and/or RNA transcripts transcribed from DNA sequences around the break sites (Fig. 1) [10,11,14].
Conflict of interest
4. Template-RNAs direct DNA repair
Acknowledgments
Several artificial RNA elements have been shown to function as direct templates for DSB repair in eukaryotic cells (13, 62, 63). This challenges the conventional wisdom that HR strand exchange occurs only between two DNA molecules. Artificial RNA species including synthetic RNAs and long RNA templates can guide genomic rearrangements [13,62]. Similar to RNA-mediated HR between molecules in RNA viruses, Storici and co-workers recently demonstrated that endogenous transcript RNA can also promote HR at DSB sites in yeast Saccharomyces cerevisiae chromosome [13,62], suggesting the generality of reversible genetic information transfer from RNA to DNA in eukaryotes. A robust genetic reporter system has been developed to directly detect HR events initiated by transcript RNA in reverse-transcription-defective yeast strains [63]. The RNA transcript templates can accomplish repair of chromosomal DSBs depending on homologous sequences instead of chromosomal loci. This type of RNA–DNA recombination is prevented by Ribonucleases H1 and H2. DSB repair prefers the classic complementary DNA intermediate pathway in H-type ribonucleases proficient cells, but it favors RNA–DNA recombination in cells defective in those ribonucleases. At the molecular level, Rad52 seems to antagonize the inhibitory effects of ribonucleases and is required for efficiently annealing of RNA to a DSB-like DNA end at least in vitro [63]. RNA-templated DSB repair brings a brand new HR repair mechanism in eukaryotic cells (Fig. 1). Given that RNA transcripts are abundant nucleic acids in living organisms, their generality and plasticity in DSB repair and impact on genome integrity warrant further detailed investigation.
We thank MM Liu and Y Li for their scientific inputs. This work was supported by 973 programs 2011CB510103, 2012CB910900, NSFC grants 31370796, 31430022, 31225015, CAS Strategic Priority Research Program XDB14030300. We apologize for not being able to cite all the publications related to this topic due to space constraints.
5. Perspectives Given the importance of DNA damage repair for the maintenance of genome integrity and the survival of a cell, cells have evolved complex repair machinery that are thought to be build up solely by proteins. Recent discoveries have revealed that RNAs including small non-coding RNAs (miRNAs and diRNAs) and template RNAs can serves as novel regulatory components in the DSB repair pathway. It will be very exciting to have future studies dissecting the molecular and biochemical underpinnings of these RNAs in DSB repair. In addition to further exploring the functions and mechanisms of the above-mentioned RNA species in regulating DSB repair, it will be most exciting to identify novel regulatory RNA elements. Long non-coding RNAs (lncRNAs) are among the most promising targets. lncRNAs are classified as RNA transcripts that are longer than 200 nt and do not have coding potential. Nearly 15,000 unique lncRNAs are predicted by the GENCODE in humans [64,65]. Accumulating evidence has reveal that lncRNAs play critical roles in various biological processes [66–69]. The rich information stored in the primary sequences and secondary/tertiary structures of lncRNAs makes them well suited to function as scaffolds for molecular interaction [64,70]. Given that DNA damage repair involves complex protein–protein and protein–DNA interactions, it will be of great interest to investigate whether lncRNAs are involved in these interactions and serve as scaffolds for the assembly of DNA repair machinery during DNA repair process. Identification of this multilayered RNA regulation of DNA damage repair will deepen our understanding how DNA repair machinery efficiently and accurately maintains genome stability.
The authors declare that they have no conflict of interest.
References [1] T. Iyama, D.M. Wilson 3rd, DNA repair mechanisms in dividing and non-dividing cells, DNA Repair (Amst.) 12 (8) (2013) 620–636. [2] J.N. Kavanagh, et al., DNA double strand break repair: a radiation perspective, Antioxid. Redox Signal. 18 (18) (2013) 2458–2472. [3] S.C. West, et al., Double-strand break repair in human cells, Cold Spring Harb. Symp. Quant. Biol. 65 (2000) 315–321. [4] V. Dion, S.M. Gasser, Chromatin movement in the maintenance of genome stability, Cell 152 (6) (2013) 1355–1364. [5] Y. Doksani, T. de Lange, The role of double-strand break repair pathways at functional and dysfunctional telomeres, Cold Spring Harb. Perspect. Biol. 6 (12) (2014). [6] F. Gong, K.M. Miller, Mammalian DNA repair: HATs and HDACs make their mark through histone acetylation, Mutat. Res. 750 (1–2) (2013) 23–30. [7] A.A. Goodarzi, P.A. Jeggo, The repair and signaling responses to DNA double-strand breaks, Adv. Genet. 82 (2013) 1–45. [8] B.D. Price, A.D. D’Andrea, Chromatin remodeling at DNA double-strand breaks, Cell 152 (6) (2013) 1344–1354. [9] J. Vignard, G. Mirey, B. Salles, Ionizing-radiation induced DNA double-strand breaks: a direct and indirect lighting up, Radiother. Oncol. 108 (3) (2013) 362–369. [10] F. d’Adda di Fagagna, A direct role for small non-coding RNAs in DNA damage response, Trends Cell Biol. 24 (3) (2014) 171–178. [11] Z. Ba, Y. Qi, Small RNAs: emerging key players in DNA double-strand break repair, Sci. China Life Sci. 56 (10) (2013) 933–936. [12] G. Wan, et al., miRNA response to DNA damage, Trends Biochem. Sci. 36 (9) (2011) 478–484. [13] H. Keskin, et al., Transcript-RNA-templated DNA. recombination and repair, Nature 515 (7527) (2014) 436–439. [14] S. Yamanaka, H. Siomi, diRNA-Ago2-RAD51 complexes at double-strand break sites, Cell Res. 24 (5) (2014) 511–512. [15] G. Bottai, et al., Targeting the microRNA-regulating DNA damage/repair pathways in cancer, Expert Opin. Biol. Ther. 14 (11) (2014) 1667–1683. [16] M. Garofalo, C.M. Croce, MicroRNAs as therapeutic targets in chemoresistance, Drug Resist. Updates 16 (3–5) (2013) 47–59. [17] C. Han, et al., Crosstalk between the DNA damage response pathway and microRNAs, Cell Mol. Life Sci. 69 (17) (2012) 2895–2906. [18] M. Ofir, D. Hacohen, D. Ginsberg, MiR-15 and miR-16 are direct transcriptional targets of E2F1 that limit E2F-induced proliferation by targeting cyclin E, Mol. Cancer Res. 9 (4) (2011) 440–447. [19] P. Wang, et al., microRNA-21 negatively regulates Cdc25A and cell cycle progression in colon cancer cells, Cancer Res. 69 (20) (2009) 8157–8165. [20] M. Liu, et al., Regulation of the cell cycle gene: BTG2, by miR-21 in human laryngeal carcinoma, Cell Res. 19 (7) (2009) 828–837. [21] D.G. Zhang, J.N. Zheng, D.S. Pei, P53/microRNA-34-induced metabolic regulation: new opportunities in anticancer therapy, Mol. Cancer 13 (2014) 115. [22] J.Y. Zhou, et al., Analysis of microRNA expression profiles during the cell cycle in synchronized HeLa cells, BMB Rep. 42 (9) (2009) 593–598. [23] X. Sun, et al., Let-7: a regulator of the ERalpha signaling pathway in human breast tumors and breast cancer stem cells, Oncol. Rep. 29 (5) (2013) 2079–2087. [24] P.E. de Oliveira, et al., Hypoxia-mediated regulation of Cdc25A phosphatase by p21 and miR-21, Cell Cycle 8 (19) (2009) 3157–3164. [25] M. Rahman, et al., miR-15b/16-2 regulates factors that promote p53 phosphorylation and augments the DNA damage response following radiation in the lung, J. Biol. Chem. 289 (38) (2014) 26406–26416. [26] X. Zhang, et al., Oncogenic Wip1 phosphatase is inhibited by miR-16 in the DNA damage signaling pathway, Cancer Res. 70 (18) (2010) 7176–7186. [27] L. Boominathan, The guardians of the genome (p53: TA-p73, and TA-p63) are regulators of tumor suppressor miRNAs network, Cancer Metastasis Rev. 29 (4) (2010) 613–639. [28] Y.H. Cha, et al., MiRNA-34 intrinsically links p53 tumor suppressor and Wnt signaling, Cell Cycle 11 (7) (2012) 1273–1281. [29] T.C. Chang, et al., Transactivation of miR-34a by p53 broadly influences gene expression and promotes apoptosis, Mol. Cell 26 (5) (2007) 745–752.
Please cite this article in press as: Y.-G. Yang, Y. Qi, RNA-directed repair of DNA double-strand breaks, DNA Repair (2015), http://dx.doi.org/10.1016/j.dnarep.2015.04.017
G Model DNAREP-2096; No. of Pages 4 4
ARTICLE IN PRESS Y.-G. Yang, Y. Qi / DNA Repair xxx (2015) xxx–xxx
[30] L. He, et al., A microRNA component of the p53 tumour suppressor network, Nature 447 (7148) (2007) 1130–1134. [31] N.H. Kim, et al., p53 regulates nuclear GSK-3 levels through miR-34-mediated Axin2 suppression in colorectal cancer cells, Cell Cycle 12 (10) (2013) 1578–1587. [32] H. Tang, et al., Let-7g microRNA sensitizes fluorouracil-resistant human hepatoma cells, Pharmazie 69 (4) (2014) 287–292. [33] A. Tzatsos, et al., Lysine-specific demethylase 2B (KDM2B)-let-7-enhancer of zester homolog 2 (EZH2) pathway regulates cell cycle progression and senescence in primary cells, J. Biol. Chem. 286 (38) (2011) 33061–33069. [34] C.D. Johnson, et al., The let-7 microRNA represses cell proliferation pathways in human cells, Cancer Res. 67 (16) (2007) 7713–7722. [35] A. Lal, et al., miR-24 Inhibits cell proliferation by targeting E2F2: MYC, and other cell-cycle genes via binding to seedless 3’UTR microRNA recognition elements, Mol. Cell 35 (5) (2009) 610–625. [36] S. Gupta, et al., Perk-dependent repression of miR-106b-25 cluster is required for ER stress-induced apoptosis, Cell Death Dis. 3 (2012) pe333. [37] M. Hackl, et al., miR-17: miR-19b, miR-20a, and miR-106a are down-regulated in human aging, Aging Cell 9 (2) (2010) 291–296. [38] P. Dmitriev, et al., Defective regulation of microRNA target genes in myoblasts from facioscapulohumeral dystrophy patients, J. Biol. Chem. 288 (49) (2013) 34989–35002. [39] A.C. Mueller, D. Sun, A. Dutta, The miR-99 family regulates the DNA damage response through its target SNF2H, Oncogene 32 (9) (2013) 1164–1172. [40] I. Ivanovska, et al., MicroRNAs in the miR-106b family regulate p21/CDKN1A and promote cell cycle progression, Mol. Cell Biol. 28 (7) (2008) 2167–2174. [41] H.I. Trompeter, et al., MicroRNAs MiR-17, MiR-20a, and MiR-106b act in concert to modulate E2F activity on cell cycle arrest during neuronal lineage differentiation of USSC, PLoS One 6 (1) (2011) e16138. [42] G. Yang, et al., MiR-106a inhibits glioma cell growth by targeting E2F1 independent of p53 status, J. Mol. Med. (Berl.) 89 (10) (2011) 1037–1050. [43] S. He, et al., Aurora kinase A induces miR-17-92 cluster through regulation of E2F1 transcription factor, Cell Mol. Life Sci. 67 (12) (2010) 2069–2076. [44] N. Cloonan, et al., The miR-17-5p microRNA is a key regulator of the G1/S phase cell cycle transition, Genome Biol. 9 (8) (2008) R127. [45] A. Di Francesco, et al., The DNA-damage response to gamma-radiation is affected by miR-27a in A549 cells, Int. J. Mol. Sci. 14 (9) (2013) 17881–17896. [46] N.T. Martin, et al., ATM-dependent MiR-335 targets CtIP and modulates the DNA damage response, PLoS Genet. 9 (5) (2013) e1003505. [47] D. Yan, et al., Targeting DNA-PKcs and ATM with miR-101 sensitizes tumors to radiation, PLoS One 5 (7) (2010) e11397. [48] F. Zhu, et al., MicroRNA-124 (miR-124) regulates Ku70 expression and is correlated with neuronal death induced by ischemia/reperfusion, J. Mol. Neurosci. 52 (1) (2014) 148–155. [49] S. Chen, et al., Radiosensitizing effects of ectopic miR-101 on non-small-cell lung cancer cells depend on the endogenous miR-101 level, Int. J. Radiat. Oncol. Biol. Phys. 81 (5) (2011) 1524–1529.
[50] Y. Wang, et al., MicroRNA-138 modulates DNA damage response by repressing histone H2AX expression, Mol. Cancer Res. 9 (8) (2011) 1100–1111. [51] A. Lal, et al., miR-24-mediated downregulation of H2AX suppresses DNA repair in terminally differentiated blood cells, Nat. Struct. Mol. Biol. 16 (5) (2009) 492–498. [52] K. Krishnan, et al., MicroRNA-182-5p targets a network of genes involved in DNA repair, RNA 19 (2) (2013) 230–242. [53] P. Moskwa, et al., miR-182-mediated downregulation of BRCA1 impacts DNA repair and sensitivity to PARP inhibitors, Mol. Cell 41 (2) (2011) 210–220. [54] Y. Wang, et al., MiR-96 downregulates REV1 and RAD51 to promote cellular sensitivity to cisplatin and PARP inhibition, Cancer Res. 72 (16) (2012) 4037–4046. [55] J. Shen, et al., A functional polymorphism in the miR-146a gene and age of familial breast/ovarian cancer diagnosis, Carcinogenesis 29 (10) (2008) 1963–1966. [56] W.J. Liu, et al., MLH1 as a direct target of MiR-155 and a potential predictor of favorable prognosis in pancreatic cancer, J. Gastrointest. Surg. 17 (8) (2013) 1399–1405. [57] N. Valeri, et al., Modulation of mismatch repair and genomic stability by miR-155, Proc. Natl. Acad. Sci. U. S. A. 107 (15) (2010) 6982–6987. (15) (2010) 6982–6987. [58] W. Wei, et al., A role for small RNAs in DNA double-strand break repair, Cell 149 (1) (2012) 101–112. [59] S. Francia, et al., Site-specific DICER and DROSHA RNA. products control the DNA-damage response, Nature 488 (7410) (2012) 231–235. [60] K.M. Michalik, R. Bottcher, K. Forstemann, A small RNA response at DNA ends in Drosophila, Nucleic Acids Res. 40 (19) (2012) 9596–9603. [61] M. Gao, et al., Ago2 facilitates Rad51 recruitment and DNA double-strand break repair by homologous recombination, Cell Res. 24 (5) (2014) 532–541. [62] F. Storici, et al., RNA-templated DNA repair, Nature 447 (7142) (2007) 338–341. [63] H. Keskin, et al., Transcript-RNA-templated DNA recombination and repair, Nature 515 (7527) (2014) 436–439. [64] T. Derrien, et al., The GENCODE v7 catalog of human long noncoding RNAs: analysis of their gene structure, evolution, and expression, Genome Res. 22 (9) (2012) 1775–1789. [65] J. Harrow, et al., GENCODE: the reference human genome annotation for The ENCODE Project, Genome Res. 22 (9) (2012) 1760–1774. [66] M. Kataoka, D.Z. Wang, Non-coding RNAs including miRNAs and lncRNAs in cardiovascular biology and disease, Cells 3 (3) (2014) 883–898. [67] M.N. Rossi, F. Antonangeli, LncRNAs: new players in apoptosis control, Int. J. Cell Biol. 2014 (2014) 473857. [68] J. Zhu, et al., Function of lncRNAs and approaches to lncRNA-protein interactions, Sci. China Life Sci. 56 (10) (2013) 876–885. [69] P.M. Guenzl, D.P. Barlow, Macro lncRNAs: a new layer of cis-regulatory information in the mammalian genome, RNA Biol. 9 (6) (2012) 731–741. [70] I.V. Novikova, et al., Rise of the RNA machines: exploring the structure of long non-coding RNAs, J. Mol. Biol. 425 (19) (2013) 3731–3746.
Please cite this article in press as: Y.-G. Yang, Y. Qi, RNA-directed repair of DNA double-strand breaks, DNA Repair (2015), http://dx.doi.org/10.1016/j.dnarep.2015.04.017