Key Points
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DNA damage processing pathways involve checkpoints for damage sensing, repair pathways for damage removal and a system of damage tolerance to bypass lesions during DNA replication.
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Non-degradative ubiquitin signalling, mediated by monoubiquitylation or polyubiquitylation through non-standard linkage, often involves the recruitment of downstream effectors that recognize relevant ubiquitylation targets by means of ubiquitin-binding domains. These domains sometimes show exquisite specificity for a particular type of chain geometry.
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The signalling events at a DNA double-strand break are mediated by a ubiquitylation cascade involving the ubiquitin protein ligases RING finger protein 8 (RNF8) and RNF168, the modification of histone H2A and the formation of Lys63-linked polyubiquitin chains on as-yet-unidentified target proteins. Collectively, they promote the recruitment of the E3 ligase breast and ovarian cancer type 1 susceptibility protein (BRCA1), which is required for G2–M checkpoint arrest and initiates break repair by homologous recombination.
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The Fanconi anaemia pathway is a replication-associated system for the processing of DNA interstrand cross links that culminates in the monoubiquitylation of the proteins Fanconi anaemia group D2 protein (FANCD2) and FANCI, resulting in their recruitment to chromatin and the initiation of recombination-mediated repair.
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Post-translational modification of the replication clamp protein proliferating cell nuclear antigen (PCNA) by monoubiquitylation and Lys63-linked polyubiquitylation controls replicative lesion bypass by translesion synthesis and an error-free, recombination-like mechanism, respectively. In budding yeast, PCNA is also subject to sumoylation, which facilitates the ubiquitin-dependent pathways by inhibiting unscheduled recombination events.
Abstract
Post-translational modification by ubiquitin is best known for its role in targeting its substrates for regulated degradation. However, non-proteolytic functions of the ubiquitin system, often involving either monoubiquitylation or polyubiquitylation through Lys63-linked chains, have emerged in various cell signalling pathways. These two forms of the ubiquitin signal contribute to three different pathways related to the maintenance of genome integrity that are responsible for the processing of DNA double-strand breaks, the repair of interstrand cross links and the bypass of lesions during DNA replication.
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References
Goldknopf, I. L. & Busch, H. Isopeptide linkage between nonhistone and histone 2A polypeptides of chromosomal conjugate-protein A24. Proc. Natl Acad. Sci. USA 74, 864–868 (1977).
Ciechanover, A., Hod, Y. & Hershko, A. A heat-stable polypeptide component of an ATP-dependent proteolytic system from reticulocytes. Biochem. Biophys. Res. Commun. 81, 1100–1105 (1978).
Hershko, A. & Ciechanover, A. The ubiquitin system. Annu. Rev. Biochem. 67, 425–479 (1998).
Schwartz, D. C. & Hochstrasser, M. A superfamily of protein tags: ubiquitin, SUMO and related modifiers. Trends Biochem. Sci. 28, 321–328 (2003).
Xu, P. et al. Quantitative proteomics reveals the function of unconventional ubiquitin chains in proteasomal degradation. Cell 137, 133–145 (2009).
Kirisako, T. et al. A ubiquitin ligase complex assembles linear polyubiquitin chains. EMBO J. 25, 4877–4887 (2006).
Ikeda, F. & Dikic, I. Atypical ubiquitin chains: new molecular signals. EMBO Rep. 9, 536–542 (2008).
Chen, Z. J. & Sun, L. J. Nonproteolytic functions of ubiquitin in cell signaling. Mol. Cell 33, 275–286 (2009).
Dikic, I., Wakatsuki, S. & Walters, K. J. Ubiquitin-binding domains — from structures to functions. Nature Rev. Mol. Cell Biol. 10, 659–671 (2009).
Komander, D. et al. Molecular discrimination of structurally equivalent Lys 63-linked and linear polyubiquitin chains. EMBO Rep. 10, 466–473 (2009).
Kulathu, Y., Akutsu, M., Bremm, A., Hofmann, K. & Komander, D. Two-sided ubiquitin binding explains specificity of the TAB2 NZF domain. Nature Struct. Mol. Biol. 16, 1328–1330 (2009).
Sato, Y. et al. Structural basis for specific recognition of Lys 63-linked polyubiquitin chains by tandem UIMs of RAP80. EMBO J. 28, 2461–2468 (2009).
Nyberg, K. A., Michelson, R. J., Putnam, C. W. & Weinert, T. A. Toward maintaining the genome: DNA damage and replication checkpoints. Annu. Rev. Genet. 36, 617–656 (2002).
Fu, Y. et al. Rad6-Rad18 mediates a eukaryotic SOS response by ubiquitinating the 9-1-1 checkpoint clamp. Cell 133, 601–611 (2008).
Davies, A. A., Neiss, A. & Ulrich, H. D. Ubiquitylation of the 9-1-1 checkpoint clamp is independent of Rad6-Rad18 and DNA damage. Cell 11 Jun 2010 (doi:10.1016/j.cell.2010.04.039).
Lindahl, T. & Wood, R. D. Quality control by DNA repair. Science 286, 1897–1905 (1999).
Bergink, S. & Jentsch, S. Principles of ubiquitin and SUMO modifications in DNA repair. Nature 458, 461–467 (2009).
Huang, T. T. & D'Andrea, A. D. Regulation of DNA repair by ubiquitylation. Nature Rev. Mol. Cell Biol. 7, 323–334 (2006).
Ben-Yehoyada, M. et al. Checkpoint signaling from a single DNA interstrand crosslink. Mol. Cell 35, 704–715 (2009).
Lawrence, C. The RAD6 DNA repair pathway in Saccharomyces cerevisiae: what does it do, and how does it do it? Bioessays 16, 253–258 (1994).
Rogakou, E. P., Pilch, D. R., Orr, A. H., Ivanova, V. S. & Bonner, W. M. DNA double-stranded breaks induce histone H2AX phosphorylation on serine 139. J. Biol. Chem. 273, 5858–5868 (1998).
Lou, Z. et al. MDC1 maintains genomic stability by participating in the amplification of ATM-dependent DNA damage signals. Mol. Cell 21, 187–200 (2006).
Stucki, M. et al. MDC1 directly binds phosphorylated histone H2AX to regulate cellular responses to DNA double-strand breaks. Cell 123, 1213–1226 (2005).
Huen, M. S. et al. RNF8 transduces the DNA-damage signal via histone ubiquitylation and checkpoint protein assembly. Cell 131, 901–914 (2007).
Kolas, N. K. et al. Orchestration of the DNA-damage response by the RNF8 ubiquitin ligase. Science 318, 1637–1640 (2007).
Mailand, N. et al. RNF8 ubiquitylates histones at DNA double-strand breaks and promotes assembly of repair proteins. Cell 131, 887–900 (2007). References 24–26 describe the identification of RNF8 as an E3 enzyme responsible for mediating checkpoint signalling by ubiquitylation.
Huen, M. S. et al. Noncanonical E2 variant-independent function of UBC13 in promoting checkpoint protein assembly. Mol. Cell. Biol. 28, 6104–6112 (2008).
Zhao, G. Y. et al. A critical role for the ubiquitin-conjugating enzyme Ubc13 in initiating homologous recombination. Mol. Cell 25, 663–675 (2007).
Stewart, G. S. et al. The RIDDLE syndrome protein mediates a ubiquitin-dependent signaling cascade at sites of DNA damage. Cell 136, 420–434 (2009).
Doil, C. et al. RNF168 binds and amplifies ubiquitin conjugates on damaged chromosomes to allow accumulation of repair proteins. Cell 136, 435–446 (2009). References 29 and 30 describe the isolation and characterization of RNF168 as a second E3 enzyme downstream of RNF8 that is involved in checkpoint signalling through Lys63-linked ubiquitylation.
Kim, H., Chen, J. & Yu, X. Ubiquitin-binding protein RAP80 mediates BRCA1-dependent DNA damage response. Science 316, 1202–1205 (2007).
Liu, Z., Wu, J. & Yu, X. CCDC98 targets BRCA1 to DNA damage sites. Nature Struct. Mol. Biol. 14, 716–720 (2007).
Sobhian, B. et al. RAP80 targets BRCA1 to specific ubiquitin structures at DNA damage sites. Science 316, 1198–1202 (2007).
Wang, B. et al. Abraxas and RAP80 form a BRCA1 protein complex required for the DNA damage response. Science 316, 1194–1198 (2007). References 31–34 describe the role of RAP80 as a ubiquitin-binding protein in the recruitment of BRCA1 to DSBs.
Feng, L., Huang, J. & Chen, J. MERIT40 facilitates BRCA1 localization and DNA damage repair. Genes Dev. 23, 719–728 (2009).
Shao, G. et al. MERIT40 controls BRCA1-Rap80 complex integrity and recruitment to DNA double-strand breaks. Genes Dev. 23, 740–754 (2009).
Wang, B., Hurov, K., Hofmann, K. & Elledge, S. J. NBA1, a new player in the Brca1 A complex, is required for DNA damage resistance and checkpoint control. Genes Dev. 23, 729–739 (2009).
Huang, J. et al. RAD18 transmits DNA damage signalling to elicit homologous recombination repair. Nature Cell Biol. 11, 592–603 (2009).
Bekker-Jensen, S. et al. HERC2 coordinates ubiquitin-dependent assembly of DNA repair factors on damaged chromosomes. Nature Cell Biol. 12, 80–86 (2009).
Deng, L. et al. Activation of the IκB kinase complex by TRAF6 requires a dimeric ubiquitin-conjugating enzyme complex and a unique polyubiquitin chain. Cell 103, 351–361 (2000).
Hofmann, R. M. & Pickart, C. M. Noncanonical MMS2-encoded ubiquitin-conjugating enzyme functions in assembly of novel polyubiquitin chains for DNA repair. Cell 96, 645–653 (1999).
VanDemark, A. P., Hofmann, R. M., Tsui, C., Pickart, C. M. & Wolberger, C. Molecular insights into polyubiquitin chain assembly: crystal structure of the Mms2/Ubc13 heterodimer. Cell 105, 711–720 (2001). The crystal structure of the Mms2–Ubc13 complex provides a mechanistic explanation for the exclusive Lys63-linkage specificity of this heterodimeric E2 enzyme.
Botuyan, M. V. et al. Structural basis for the methylation state-specific recognition of histone H4-K20 by 53BP1 and Crb2 in DNA repair. Cell 127, 1361–1373 (2006).
Vissers, J. H., Nicassio, F., van Lohuizen, M., Di Fiore, P. P. & Citterio, E. The many faces of ubiquitinated histone H2A: insights from the DUBs. Cell Div. 3, 8 (2008).
Nicassio, F. et al. Human USP3 is a chromatin modifier required for S phase progression and genome stability. Curr. Biol. 17, 1972–1977 (2007).
Galanty, Y. et al. Mammalian SUMO E3-ligases PIAS1 and PIAS4 promote responses to DNA double-strand breaks. Nature 462, 935–939 (2009).
Morris, J. R. et al. The SUMO modification pathway is involved in the BRCA1 response to genotoxic stress. Nature 462, 886–890 (2009).
Huen, M. S., Sy, S. M. H. & Chen, J. BRCA1 and its toolbox for the maintenance of genome integrity. Nature Rev. Mol. Cell Biol. 11, 138–148 (2010).
Stewart, G. S. et al. RIDDLE immunodeficiency syndrome is linked to defects in 53BP1-mediated DNA damage signaling. Proc. Natl Acad. Sci. USA 104, 16910–16915 (2007).
Marteijn, J. A. et al. Nucleotide excision repair-induced H2A ubiquitination is dependent on MDC1 and RNF8 and reveals a universal DNA damage response. J. Cell Biol. 186, 835–847 (2009).
Lilley, C. E. et al. A viral E3 ligase targets RNF8 and RNF168 to control histone ubiquitination and DNA damage responses. EMBO J. 29, 943–955 (2010).
Tremblay, C. S. et al. The Fanconi anemia core complex acts as a transcriptional co-regulator in hairy enhancer of split 1 signaling. J. Biol. Chem. 284, 13384–13395 (2009).
Tremblay, C. S. et al. HES1 is a novel interactor of the Fanconi anemia core complex. Blood 112, 2062–2070 (2008).
Alpi, A. F. & Patel, K. J. Monoubiquitylation in the Fanconi anemia DNA damage response pathway. DNA Repair 8, 430–435 (2009).
Moldovan, G. L. & D'Andrea, A. D. How the fanconi anemia pathway guards the genome. Annu. Rev. Genet. 43, 223–249 (2009).
Smogorzewska, A. et al. Identification of the FANCI protein, a monoubiquitinated FANCD2 paralog required for DNA repair. Cell 129, 289–301 (2007).
Garcia-Higuera, I. et al. Interaction of the Fanconi anemia proteins and BRCA1 in a common pathway. Mol. Cell 7, 249–262 (2001). This study is the first to show that Fanconi anaemia proteins operate in a common pathway to monoubiquitylate FANCD2.
Meetei, A. R. et al. A human ortholog of archaeal DNA repair protein Hef is defective in Fanconi anemia complementation group, M. Nature Genet. 37, 958–963 (2005).
Kim, J. M., Kee, Y., Gurtan, A. & D'Andrea, A. D. Cell cycle-dependent chromatin loading of the Fanconi anemia core complex by FANCM/FAAP24. Blood 111, 5215–5222 (2008).
Ciccia, A. et al. Identification of FAAP24, a Fanconi anemia core complex protein that interacts with FANCM. Mol. Cell 25, 331–343 (2007).
Xue, Y., Li, Y., Guo, R., Ling, C. & Wang, W. FANCM of the Fanconi anemia core complex is required for both monoubiquitination and DNA repair. Hum. Mol. Genet. 17, 1641–1652 (2008).
Deans, A. J. & West, S. C. FANCM connects the genome instability disorders Bloom's syndrome and Fanconi anemia. Mol. Cell 36, 943–953 (2009).
Schwab, R. A., Blackford, A. N. & Niedzwiedz, W. ATR activation and replication fork restart are defective in FANCM-deficient cells. EMBO J. 29, 806–818 (2010).
Luke-Glaser, S., Luke, B., Grossi, S. & Constantinou, A. FANCM regulates DNA chain elongation and is stabilized by S-phase checkpoint signalling. EMBO J. 29, 795–805 (2010).
Singh, T. R. et al. MHF1-MHF2, a histone-fold-containing protein complex, participates in the Fanconi anemia pathway via FANCM. Mol. Cell 37, 879–886 (2010).
Yan, Z. et al. A histone-fold complex and FANCM form a conserved DNA-remodeling complex to maintain genome stability. Mol. Cell 37, 865–878 (2010).
Meetei, A. R. et al. A novel ubiquitin ligase is deficient in Fanconi anemia. Nature Genet. 35, 165–170 (2003). Identification of the catalytic subunit of the Fanconi anaemia core complex in this study provides direct evidence of ubiquitin ligase activity.
Machida, Y. J. et al. UBE2T is the E2 in the Fanconi anemia pathway and undergoes negative autoregulation. Mol. Cell 23, 589–596 (2006).
Alpi, A. F., Pace, P. E., Babu, M. M. & Patel, K. J. Mechanistic insight into site-restricted monoubiquitination of FANCD2 by Ube2t, FANCL, and FANCI. Mol. Cell 32, 767–777 (2008). In vitro reconstitution of FANCD2 monoubiquitylation provides evidence of the minimum requirements for reaction.
Ishiai, M. et al. FANCI phosphorylation functions as a molecular switch to turn on the Fanconi anemia pathway. Nature Struct. Mol. Biol. 15, 1138–1146 (2008).
Longerich, S., San Filippo, J., Liu, D. & Sung, P. FANCI binds branched DNA and is monoubiquitinated by UBE2T-FANCL. J. Biol. Chem. 284, 23182–23186 (2009).
Cole, A. R., Lewis, L. P. C. & Walden, H. The structure of the catalytic subunit FANCL of the Fanconi anemia core complex. Nature Struct. Mol. Biol. 17, 294–298 (2010).
Ueki, T. et al. Ubiquitination and downregulation of BRCA1 by ubiquitin-conjugating enzyme E2T overexpression in human breast cancer cells. Cancer Res. 69, 8752–8760 (2009).
Matsushita, N. et al. A FancD2-monoubiquitin fusion reveals hidden functions of Fanconi anemia core complex in DNA repair. Mol. Cell 19, 841–847 (2005).
Knipscheer, P. et al. The Fanconi anemia pathway promotes replication-dependent DNA interstrand cross-link repair. Science 326, 1698–1701 (2009). An ICL repair assay based on X. laevis egg extracts provides direct evidence of the requirement for FANCI and FANCD2 for ICL repair in S phase.
Raschle, M. et al. Mechanism of replication-coupled DNA interstrand crosslink repair. Cell 134, 969–980 (2008).
Oestergaard, V. H. et al. Deubiquitination of FANCD2 is required for DNA crosslink repair. Mol. Cell 28, 798–809 (2007).
Nijman, S. M. et al. The deubiquitinating enzyme USP1 regulates the Fanconi anemia pathway. Mol. Cell 17, 331–339 (2005).
Kim, J. M. et al. Inactivation of murine Usp1 results in genomic instability and a Fanconi anemia phenotype. Dev. Cell 16, 314–320 (2009).
Moldovan, G. L. & D'Andrea, A. D. FANCD2 hurdles the DNA interstrand crosslink. Cell 139, 1222–1224 (2009).
van Leuken, R., Clijsters, L. & Wolthuis, R. To cell cycle, swing the APC/C. Biochim. Biophys. Acta 1786, 49–59 (2008).
Vanderwerf, S. M. et al. TLR8-dependent TNF-α overexpression in Fanconi anemia group C cells. Blood 114, 5290–5298 (2009).
Ulrich, H. D. Regulating post-translational modifications of the eukaryotic replication clamp PCNA. DNA Repair 8, 461–469 (2009).
Hoege, C., Pfander, B., Moldovan, G. L., Pyrowolakis, G. & Jentsch, S. RAD6-dependent DNA repair is linked to modification of PCNA by ubiquitin and SUMO. Nature 419, 135–141 (2002). This study identifies PCNA as the relevant target for ubiquitylation in the context of DNA damage bypass.
Kannouche, P. L., Wing, J. & Lehmann, A. R. Interaction of human DNA polymerase η with monoubiquitinated PCNA: a possible mechanism for the polymerase switch in response to DNA damage. Mol. Cell 14, 491–500 (2004).
Watanabe, K. et al. Rad18 guides polη to replication stalling sites through physical interaction and PCNA monoubiquitination. EMBO J. 23, 3886–3896 (2004).
Stelter, P. & Ulrich, H. D. Control of spontaneous and damage-induced mutagenesis by SUMO and ubiquitin conjugation. Nature 425, 188–191 (2003). References 85–87 provide biochemical and genetic evidence that PCNA monoubiquitylation activates TLS.
Chen, C. C. et al. Genetic analysis of ionizing radiation-induced mutagenesis in Saccharomyces cerevisiae reveals translesion synthesis (TLS) independent of PCNA K164 SUMOylation and ubiquitination. DNA Repair 5, 1475–1488 (2006).
Edmunds, C. E., Simpson, L. J. & Sale, J. E. PCNA ubiquitination and REV1 define temporally distinct mechanisms for controlling translesion synthesis in the avian cell line DT40. Mol. Cell 30, 519–529 (2008).
Okada, T. et al. Involvement of vertebrate polκ in Rad18-independent postreplication repair of UV damage. J. Biol. Chem. 277, 48690–48695 (2002).
Arakawa, H. et al. A role for PCNA ubiquitination in immunoglobulin hypermutation. PLoS Biol. 4, e366 (2006).
Bienko, M. et al. Ubiquitin-binding domains in Y-family polymerases regulate translesion synthesis. Science 310, 1821–1824 (2005). UBDs are identified in a family of damage-tolerant polymerases, thus revealing the mechanism by which ubiquitylated PCNA activates TLS.
Hishida, T., Kubota, Y., Carr, A. M. & Iwasaki, H. RAD6-RAD18-RAD5-pathway-dependent tolerance to chronic low-dose ultraviolet light. Nature 457, 612–615 (2009).
Zhao, S. & Ulrich, H. D. Distinct consequences of post-translational modification by linear versus K63-linked polyubiquitin chains. Proc. Natl Acad. Sci. USA 107, 7704–7709 (2010).
Papouli, E. et al. Crosstalk between SUMO and ubiquitin on PCNA is mediated by recruitment of the helicase Srs2p. Mol. Cell 19, 123–133 (2005).
Pfander, B., Moldovan, G. L., Sacher, M., Hoege, C. & Jentsch, S. SUMO-modified PCNA recruits Srs2 to prevent recombination during S phase. Nature 436, 428–433 (2005).
Moldovan, G. L., Pfander, B. & Jentsch, S. PCNA controls establishment of sister chromatid cohesion during S phase. Mol. Cell 23, 723–732 (2006).
Garg, P. & Burgers, P. M. Ubiquitinated proliferating cell nuclear antigen activates translesion DNA polymerases η and REV1. Proc. Natl Acad. Sci. USA 102, 18361–18366 (2005).
Parker, J. L. et al. SUMO modification of PCNA is controlled by DNA. EMBO J. 27, 2422–2431 (2008).
Carlile, C. M., Pickart, C. M., Matunis, M. J. & Cohen, R. E. Synthesis of free and proliferating cell nuclear antigen-bound polyubiquitin chains by the RING E3 ubiquitin ligase Rad5. J. Biol. Chem. 284, 29326–29334 (2009).
Parker, J. L. & Ulrich, H. D. Mechanistic analysis of PCNA poly-ubiquitylation by the ubiquitin protein ligases Rad18 and Rad5. EMBO J. 28, 3657–3666 (2009).
Davies, A. A., Huttner, D., Daigaku, Y., Chen, S. & Ulrich, H. D. Activation of ubiquitin-dependent DNA damage bypass is mediated by replication protein a. Mol. Cell 29, 625–636 (2008).
Niimi, A. et al. Regulation of proliferating cell nuclear antigen ubiquitination in mammalian cells. Proc. Natl Acad. Sci. USA 105, 16125–16130 (2008).
Chang, D. J., Lupardus, P. J. & Cimprich, K. A. Monoubiquitination of proliferating cell nuclear antigen induced by stalled replication requires uncoupling of DNA polymerase and mini-chromosome maintenance helicase activities. J. Biol. Chem. 281, 32081–32088 (2006).
Frampton, J. et al. Postreplication repair and PCNA modification in Schizosaccharomyces pombe. Mol. Biol. Cell 17, 2976–2985 (2006).
Daigaku, Y., Davies, A. A. & Ulrich, H. D. Ubiquitin-dependent DNA damage bypass is separable from genome replication. Nature 9 May 2010 (doi:10.1038/nature09097).
Karras, G. I. & Jentsch, S. The RAD6 DNA damage tolerance pathway operates uncoupled from the replication fork and is functional beyond S phase. Cell 141, 255–267 (2010). References 106 and 107 provide evidence that both TLS and error-free damage bypass can be delayed until after genome replication without adverse effects in yeast.
Waters, L. S. & Walker, G. C. The critical mutagenic translesion DNA polymerase Rev1 is highly expressed during G 2/M phase rather than S phase. Proc. Natl Acad. Sci. USA 103, 8971–8976 (2006).
Huang, T. T. et al. Regulation of monoubiquitinated PCNA by DUB autocleavage. Nature Cell Biol. 8, 339–347 (2006).
Yang, X. H., Shiotani, B., Classon, M. & Zou, L. Chk1 and Claspin potentiate PCNA ubiquitination. Genes Dev. 22, 1147–1152 (2008).
Bi, X. et al. Rad18 regulates DNA polymerase κ and is required for recovery from S-phase checkpoint-mediated arrest. Mol. Cell. Biol. 26, 3527–3540 (2006).
Simpson, L. J. et al. RAD18-independent ubiquitination of proliferating-cell nuclear antigen in the avian cell line DT40. EMBO Rep. 7, 927–932 (2006).
Terai, K., Abbas, T., Jazaeri, A. A. & Dutta, A. CRL4Cdt2 E3 ubiquitin ligase monoubiquitinates PCNA to promote translesion DNA synthesis. Mol. Cell 37, 143–149 (2010).
Zhang, S. et al. PCNA is ubiquitinated by RNF8. Cell Cycle 7, 3399–3404 (2008).
Das-Bradoo, S. et al. Defects in DNA ligase I trigger PCNA ubiquitylation at Lys 107. Nature Cell Biol. 12, 74–79 (2010).
Chen, J., Ai, Y., Wang, J., Haracska, L. & Zhuang, Z. Chemically ubiquitylated PCNA as a probe for eukaryotic translesion DNA synthesis. Nature Chem. Biol. 6, 270–272 (2010).
Freudenthal, B. D., Gakhar, L., Ramaswamy, S. & Washington, M. T. Structure of monoubiquitinated PCNA and implications for translesion synthesis and DNA polymerase exchange. Nature Struct. Mol. Biol. 17, 479–484 (2010).
Cohen, P. The origins of protein phosphorylation. Nature Cell Biol. 4, E127–E130 (2002).
Paik, W. K., Paik, D. C. & Kim, S. Historical review: the field of protein methylation. Trends Biochem. Sci. 32, 146–152 (2007).
Mellert, H. S. & McMahon, S. B. Biochemical pathways that regulate acetyltransferase and deacetylase activity in mammalian cells. Trends Biochem. Sci. 34, 571–578 (2009).
Christensen, D. E., Brzovic, P. S. & Klevit, R. E. E2-BRCA1 RING interactions dictate synthesis of mono- or specific polyubiquitin chain linkages. Nature Struct. Mol. Biol. 14, 941–948 (2007).
Yu, X., Fu, S., Lai, M., Baer, R. & Chen, J. BRCA1 ubiquitinates its phosphorylation-dependent binding partner CtIP. Genes Dev. 20, 1721–1726 (2006).
Reid, L. J. et al. E3 ligase activity of BRCA1 is not essential for mammalian cell viability or homology-directed repair of double-strand DNA breaks. Proc. Natl Acad. Sci. USA 105, 20876–20881 (2008).
Sy, S. M., Huen, M. S. & Chen, J. PALB2 is an integral component of the BRCA complex required for homologous recombination repair. Proc. Natl Acad. Sci. USA 106, 7155–7160 (2009).
Zhang, F. et al. PALB2 links BRCA1 and BRCA2 in the DNA-damage response. Curr. Biol. 19, 524–529 (2009).
Wang, W. Emergence of a DNA-damage response network consisting of Fanconi anaemia and BRCA proteins. Nature Rev. Genet. 8, 735–748 (2007).
Szuts, D., Simpson, L. J., Kabani, S., Yamazoe, M. & Sale, J. E. Role for RAD18 in homologous recombination in DT40 cells. Mol. Cell. Biol. 26, 8032–8041 (2006).
McKee, R. H. & Lawrence, C. W. Genetic analysis of gamma-ray mutagenesis in yeast. III. Double-mutant strains. Mutat. Res. 70, 37–48 (1980).
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Supplementary information S2 (table) | Sources for the structural models used in supplementary information S1 (figure), S3 (figure) and S4 (figure). (PDF 226 kb)
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Glossary
- Ubiquitin-binding domain
-
(UBD). A domain that mediates non-covalent interactions with ubiquitin. UBDs are usually found in downstream effectors that selectively interact with ubiquitylated target proteins and come in various different types (reviewed in Ref. 9), such as α-helical motifs in UBM, UIM and MIU, or zinc fingers, as in UBZ.
- Replication fork
-
The part of replicating DNA in which the two strands are being separated and DNA synthesis is occurring to generate two copies of the parental DNA.
- Homologous recombination
-
Genetic recombination process in which nucleotide sequences are exchanged between two strands of identical or similar DNA. This pathway is widely used in repairing DSBs.
- Non-homologous end joining
-
A means to repair DSBs that is alternative to homologous recombination and involves direct ligation of the break ends without the need for a homologous template.
- Base excision repair
-
A DNA repair pathway that is primarily responsible for removing small, non-helix-distorting base lesions that affect only one strand, such as alkylation or oxidative damage.
- Nucleotide excision repair
-
A pathway responsible for the removal of bulky, helix-distorting lesions that affect only one strand, involving the excision of a lesion-containing oligonucleotide and the resynthesis of the affected region.
- FHA
-
A 65–100-residue phosphorylation-specific protein–protein interaction motif that was first identified in forkhead transcription factors. It is often found in proteins that also contain BRCT repeats.
- BRCT
-
A ∼90-residue phosphate-binding tandem domain that interacts with specific motifs in their phosphorylated form, such as in γ-H2AX.
- RING
-
A zinc-binding protein–protein interaction motif found in RING-type E3 enzymes that scaffolds two zinc ions and forms the hallmark of the largest class of E3 ligases.
- HECT
-
A domain with a catalytic Cys residue (found in a class of E3 enzymes) that forms a thioester intermediate during ubiquitin transfer to the substrate protein.
- WD40 repeat
-
Repeat of ∼40 amino acids with a characteristic central Trp–Asp motif.
- Translesion synthesis
-
The processing of a lesion-containing replication template by a damage-tolerant polymerase that inserts either correct or inappropriate nucleotides opposite the lesion, thus potentially contributing to damage-induced mutagenesis.
- 26S proteasome
-
A large multisubunit protease complex that selectively degrades polyubiquitylated proteins.
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Ulrich, H., Walden, H. Ubiquitin signalling in DNA replication and repair. Nat Rev Mol Cell Biol 11, 479–489 (2010). https://doi.org/10.1038/nrm2921
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DOI: https://doi.org/10.1038/nrm2921
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