Ubiquitylation at Stressed Replication Forks: Mechanisms and Functions
2021; Elsevier BV; Volume: 31; Issue: 7 Linguagem: Inglês
10.1016/j.tcb.2021.01.008
ISSN1879-3088
AutoresAnn Schirin Mirsanaye, Dimitris Typas, Niels Mailand,
Tópico(s)Genetics and Neurodevelopmental Disorders
ResumoUbiquitin modifications dynamically impact the composition and functionality of both unperturbed and stressed replication forks.Ubiquitylation of major replisome platforms including proliferating cell nuclear antigen (PCNA), replication protein A (RPA), and FANCI–FANCD2 (Fanconi anemia group I protein–Fanconi anemia group D2 protein), enables recruitment of multiple effector proteins involved in overcoming diverse types of impediments to replication fork progression.A range of E3 ubiquitin ligases and ubiquitin-binding proteins promote fork reversal and protection upon replication stress.Both fork-stalling lesions that can be directly bypassed by the replicative CMG helicase and those requiring prior processing (e.g., interstrand and DNA-protein crosslinks) require ubiquitin signaling for preservation of replication integrity.Ubiquitylation of CMG is essential for its unloading upon fork convergence during replication termination and DNA interstrand crosslink repair. Accurate duplication of chromosomal DNA is vital for faithful transmission of the genome during cell division. However, DNA replication integrity is frequently challenged by genotoxic insults that compromise the progression and stability of replication forks, posing a threat to genome stability. It is becoming clear that the organization of the replisome displays remarkable flexibility in responding to and overcoming a wide spectrum of fork-stalling insults, and that these transactions are dynamically orchestrated and regulated by protein post-translational modifications (PTMs) including ubiquitylation. In this review, we highlight and discuss important recent advances on how ubiquitin-mediated signaling at the replication fork plays a crucial multifaceted role in regulating replisome composition and remodeling its configuration upon replication stress, thereby ensuring high-fidelity duplication of the genome. Accurate duplication of chromosomal DNA is vital for faithful transmission of the genome during cell division. However, DNA replication integrity is frequently challenged by genotoxic insults that compromise the progression and stability of replication forks, posing a threat to genome stability. It is becoming clear that the organization of the replisome displays remarkable flexibility in responding to and overcoming a wide spectrum of fork-stalling insults, and that these transactions are dynamically orchestrated and regulated by protein post-translational modifications (PTMs) including ubiquitylation. In this review, we highlight and discuss important recent advances on how ubiquitin-mediated signaling at the replication fork plays a crucial multifaceted role in regulating replisome composition and remodeling its configuration upon replication stress, thereby ensuring high-fidelity duplication of the genome. Precise and complete replication of cellular DNA during the S phase of each cell cycle is essential for genome stability, cell proliferation, and organismal fitness. The DNA replication process commences prior to S phase, when replication origins are licensed by the loading of inactive double minichromosome maintenance complex (MCM)2–7 hexamers [1.Evrin C. et al.A double-hexameric MCM2-7 complex is loaded onto origin DNA during licensing of eukaryotic DNA replication.Proc. Natl. Acad. Sci. U. S. A. 2009; 106: 20240-20245Crossref PubMed Scopus (347) Google Scholar, 2.Li N. et al.Structure of the eukaryotic MCM complex at 3.8 A.Nature. 2015; 524: 186-191Crossref PubMed Scopus (135) Google Scholar, 3.Remus D. et al.Concerted loading of Mcm2-7 double hexamers around DNA during DNA replication origin licensing.Cell. 2009; 139: 719-730Abstract Full Text Full Text PDF PubMed Scopus (420) Google Scholar]. In S phase, origin firing converts these double hexamers into active, bidirectional replication forks, through the recruitment of CDC45 and the GINS complex, leading to formation of the replicative CDC45–MCM2–7–GINS (CMG) helicase that translocates on the leading strand to unwind the duplex DNA template [4.Douglas M.E. et al.The mechanism of eukaryotic CMG helicase activation.Nature. 2018; 555: 265-268Crossref PubMed Scopus (69) Google Scholar,5.Ilves I. et al.Activation of the MCM2-7 helicase by association with Cdc45 and GINS proteins.Mol. Cell. 2010; 37: 247-258Abstract Full Text Full Text PDF PubMed Scopus (383) Google Scholar]. Although eukaryotic DNA replication initiates from multiple replication origins, only a fraction of licensed origins fire during a normal S phase. However, when obstacles that hinder replication fork progression are encountered, activation of otherwise dormant nearby origins provides an important rescue mechanism for completing genome duplication [6.Yekezare M. et al.Controlling DNA replication origins in response to DNA damage - inhibit globally, activate locally.J. Cell Sci. 2013; 126: 1297-1306Crossref PubMed Scopus (77) Google Scholar]. In S phase, the active replisome, consisting of the CMG helicase, replicative DNA polymerases, the replication factor C (RFC)-loaded clamp proliferating cell nuclear antigen (PCNA), and auxiliary factors, regulates every aspect of bidirectional replication, which occurs continuously on the leading strand and discontinuously on the lagging strand [7.Burgers P.M.J. Kunkel T.A. Eukaryotic DNA replication fork.Annu. Rev. Biochem. 2017; 86: 417-438Crossref PubMed Scopus (163) Google Scholar]. Deregulation of DNA replication, giving rise to replication stress (see Glossary), is a hallmark of cancer cells and a recognized driver of genomic instability [8.Gaillard H. et al.Replication stress and cancer.Nat. Rev. Cancer. 2015; 15: 276-289Crossref PubMed Scopus (375) Google Scholar, 9.Hanahan D. Weinberg R.A. Hallmarks of cancer: the next generation.Cell. 2011; 144: 646-674Abstract Full Text Full Text PDF PubMed Scopus (33467) Google Scholar, 10.Zeman M.K. Cimprich K.A. Causes and consequences of replication stress.Nat. Cell Biol. 2014; 16: 2-9Crossref PubMed Scopus (844) Google Scholar], representing an attractive target for clinical intervention. However, given the sheer size and complex organization of vertebrate genomes, low levels of replication stress occur naturally in most proliferating cells, arising due to obstacles including heterochromatin-imposed barriers (e.g., repetitive DNA sequences and G4 quadruplexes), replication-transcription collisions, ribonucleotide misincorporation, modified or mismatched nucleotides, and helix-distorting adducts that stall the advancing replication machinery [10.Zeman M.K. Cimprich K.A. Causes and consequences of replication stress.Nat. Cell Biol. 2014; 16: 2-9Crossref PubMed Scopus (844) Google Scholar]. Under normal conditions, such impediments are quickly resolved by replisome-associated factors, mismatch and excision repair pathways, or converging forks that complete replication downstream of blocked or inactive forks. Exacerbated replication stress, induced by oncogenes that deregulate the physiological DNA replication program, or exogenous agents, including mainstay chemotherapeutic drugs that drain essential DNA replication resources such as dNTP pools or generate replication fork barriers in the form of challenging DNA lesions [e.g., DNA interstrand crosslinks (ICLs) and DNA-protein crosslinks (DPCs)], may necessitate more extensive remodeling of replication fork structure and composition [10.Zeman M.K. Cimprich K.A. Causes and consequences of replication stress.Nat. Cell Biol. 2014; 16: 2-9Crossref PubMed Scopus (844) Google Scholar, 11.Ceccaldi R. et al.The Fanconi anaemia pathway: new players and new functions.Nat. Rev. Mol. Cell Biol. 2016; 17: 337-349Crossref PubMed Scopus (299) Google Scholar, 12.Kuhbacher U. Duxin J.P. How to fix DNA-protein crosslinks.DNA Repair (Amst). 2020; 94: 102924Crossref PubMed Scopus (1) Google Scholar] (Figure 1A–C ). Accordingly, cells employ sophisticated rescue mechanisms for dealing with the threats posed by a diverse range of genotoxic insults encountered by replication forks. These processes are dynamically orchestrated and regulated by protein PTMs, in particular phosphorylation and ubiquitylation. Protein modification by ubiquitin is a versatile regulatory mechanism that is mediated by an extensive network of enzymatic activities and impacts virtually all cellular processes (Box 1) [13.Oh E. et al.Principles of ubiquitin-dependent signaling.Annu. Rev. Cell Dev. Biol. 2018; 34: 137-162Crossref PubMed Scopus (81) Google Scholar]. While the indispensable roles of ubiquitin and the small ubiquitin-like modifier (SUMO) in the cellular response to DNA damage, particularly DNA double-strand breaks (DSBs), have been extensively characterized [14.Jackson S.P. Durocher D. Regulation of DNA damage responses by ubiquitin and SUMO.Mol. Cell. 2013; 49: 795-807Abstract Full Text Full Text PDF PubMed Scopus (400) Google Scholar,15.Schwertman P. et al.Regulation of DNA double-strand break repair by ubiquitin and ubiquitin-like modifiers.Nat. Rev. Mol. Cell Biol. 2016; 17: 379-394Crossref PubMed Scopus (163) Google Scholar], their involvement in responses to replication stress has remained less well defined. However, a flurry of recent discoveries now paints a more detailed picture of the crucial functions of replisome-associated ubiquitylation processes, the factors involved, and their multifaceted underlying mechanisms in promoting protective responses to many types of fork-stalling insults (Figure 1, Figure 2 and Table 1).Box 1The Ubiquitin SystemCovalent modification of cellular proteins with the small and highly conserved polypeptide ubiquitin, termed ubiquitylation, is a universal signaling mechanism affecting virtually all aspects of cell biology. Conjugation of ubiquitin to lysine residues in target proteins proceeds via a three-step relay involving numerous combinations of E1 ubiquitin-activating (Figure IA), E2 ubiquitin-conjugating (Figure IB), and RING- or HECT-type E3 ligase (Figure IC) enzymes, which act sequentially to catalyze the modification of tens of thousands of lysine residues distributed among a sheer number of substrates in human cells [13.Oh E. et al.Principles of ubiquitin-dependent signaling.Annu. Rev. Cell Dev. Biol. 2018; 34: 137-162Crossref PubMed Scopus (81) Google Scholar,114.Swatek K.N. Komander D. Ubiquitin modifications.Cell Res. 2016; 26: 399-422Crossref PubMed Scopus (562) Google Scholar]. The resulting ubiquitin marks can be removed by deubiquitylating enzymes (DUBs) (Figure ID), rendering ubiquitylation a highly dynamic and reversible protein modification [115.Clague M.J. et al.Breaking the chains: deubiquitylating enzyme specificity begets function.Nat. Rev. Mol. Cell Biol. 2019; 20: 338-352Crossref PubMed Scopus (132) Google Scholar]. Adding further complexity to the versatility of ubiquitin-mediated signaling processes, ubiquitin is not only attached as single moieties (monoubiquitylation) but can also be conjugated to any of the seven lysine residues or the N-terminal methionine within ubiquitin itself, giving rise to eight possible distinct polyubiquitin chain conformations, all of which are formed in cells and serve defined, but not in all cases well understood, cellular functions. For instance, K48- and K11-linked ubiquitin chains are major signals for degradation via the 26S proteasome, whereas K63-linked ubiquitylation is a non-proteolytic modification with critical regulatory roles in many cellular processes [13.Oh E. et al.Principles of ubiquitin-dependent signaling.Annu. Rev. Cell Dev. Biol. 2018; 34: 137-162Crossref PubMed Scopus (81) Google Scholar,114.Swatek K.N. Komander D. Ubiquitin modifications.Cell Res. 2016; 26: 399-422Crossref PubMed Scopus (562) Google Scholar]. These complex modifications underlie a cellular 'ubiquitin code' that is read and decoded by hundreds of proteins containing ubiquitin-binding domains (UBDs) (Figure IE), coupling specific ubiquitin modifications to downstream effector pathways [116.Husnjak K. Dikic I. Ubiquitin-binding proteins: decoders of ubiquitin-mediated cellular functions.Annu. Rev. Biochem. 2012; 81: 291-322Crossref PubMed Scopus (440) Google Scholar]. Approximate numbers of different classes of ubiquitin signaling enzymes encoded by human cells are indicated in red.Figure IThe Ubiquitin Modification Cycle.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Figure 2Regulatory Principles of Ubiquitylation at Stressed Replication Forks.Show full captionUbiquitylation orchestrates and regulates protein interactions with stressed replication forks via several regulatory principles to promote responses to fork-stalling insults. Fork-associated ubiquitylation processes generate recruitment platforms for a range of effector proteins, exemplified by PCNA monoubiquitylation-dependent recruitment of Y-family TLS polymerases (A). Ubiquitylation also plays active roles in removing proteins residing in the context of the replisome and antagonizing protein interactions with the fork (e.g., via proteolytic cleavage of polymerase-blocking DPCs) (B) or ubiquitin-dependent shielding of protein interaction modules such as a UBD in SPRTN, thereby blocking its access to chromatin (C). Ubiquitylation can also serve a structural role in overcoming fork-stalling lesions (e.g., by locking the FANCI–FANCD2 complex on DNA in a pin-like fashion) (D). p97 extracts many ubiquitylated replisome components including CMG from the fork (E), and the length and conformation of ubiquitin conjugates can centrally influence repair pathway choice at stalled forks, such as during ICL repair where short TRAIP-generated ubiquitin chains on CMG are recognized by NEIL3 for direct ICL reversal, whereas longer chains enable p97 recruitment to promote CMG unloading and ICL repair via the FA pathway (F). Abbreviations: CMG, CDC45–MCM2–7–GINS; DPCs, DNA-protein crosslinks; FA, Fanconi Anemia; FANCI–FANCD2, Fanconi anemia group I protein–Fanconi anemia group D2 protein); ICLs, interstrand crosslinks; PCNA, proliferating cell nuclear antigen; SPRTN, SprT-like N-terminal domain; TLS, translesion DNA synthesis; UBD, ubiquitin-binding domain.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Table 1Writers, Readers and Erasers of Replication Fork-Associated UbiquitylationFactorFunctionRefsWritersTRAIPUbiquitylates CMG on the leading strand in the presence of helicase-blocking obstacles including ICLs and DPCs. Defines a mitotic backup pathway for CMG unloading[30.Wu R.A. et al.TRAIP is a master regulator of DNA interstrand crosslink repair.Nature. 2019; 567: 267-272Crossref PubMed Scopus (48) Google Scholar,61.Larsen N.B. et al.Replication-coupled DNA-protein crosslink repair by SPRTN and the proteasome in Xenopus Egg Extracts.Mol. 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Genet. 2016; 48: 36-43Crossref PubMed Scopus (48) Google Scholar]RFWD3Ubiquitylates ssDNA-bound RPA complexes in a non-proteolytic manner to promote DNA damage bypass and fork restart[38.Elia A.E. et al.RFWD3-dependent ubiquitination of RPA regulates repair at stalled replication forks.Mol. Cell. 2015; 60: 280-293Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar,40.Feeney L. et al.RPA-mediated recruitment of the E3 ligase RFWD3 is vital for interstrand crosslink repair and human health.Mol. Cell. 2017; 66: 610-621.e4Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar, 41.Lin Y.C. et al.PCNA-mediated stabilization of E3 ligase RFWD3 at the replication fork is essential for DNA replication.Proc. Natl. Acad. Sci. U. S. A. 2018; 115: 13282-13287Crossref PubMed Scopus (10) Google Scholar, 42.Inano S. et al.RFWD3-mediated ubiquitination promotes timely removal of both RPA and RAD51 from DNA damage sites to facilitate homologous recombination.Mol. Cell. 2017; 66: 622-634.e8Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar, 43.Duan H. et al.E3 ligase RFWD3 is a novel modulator of stalled fork stability in BRCA2-deficient cells.J. Cell Biol. 2020; 219e201908192Crossref PubMed Google Scholar, 44.Knies K. et al.Biallelic mutations in the ubiquitin ligase RFWD3 cause Fanconi anemia.J. Clin. Invest. 2017; 127: 3013-3027Crossref PubMed Scopus (98) Google Scholar, 45.Gallina I. et al.The ubiquitin ligase RFWD3 is required for translesion DNA synthesis.Mol. Cell. 2020; 81: 1-17Google Scholar]RAD18Monoubiquitylates PCNA to stimulate TLS[53.Choe K.N. Moldovan G.L. Forging ahead through darkness: PCNA, still the principal conductor at the replication fork.Mol. Cell. 2017; 65: 380-392Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar,54.Garcia-Rodriguez N. et al.Functions of ubiquitin and SUMO in DNA replication and replication stress.Front. Genet. 2016; 7: 87Crossref PubMed Scopus (0) Google Scholar]HLTFPromotes PCNA polyubiquitylation to promote error-free fork restart. Recognizes free 3′-OH ends in DNA and catalyzes fork reversal[56.Motegi A. et al.Polyubiquitination of proliferating cell nuclear antigen by HLTF and SHPRH prevents genomic instability from stalled replication forks.Proc. Natl. Acad. Sci. U. S. A. 2008; 105: 12411-12416Crossref PubMed Scopus (183) Google Scholar,58.Unk I. et al.Human HLTF functions as a ubiquitin ligase for proliferating cell nuclear antigen polyubiquitination.Proc. Natl. Acad. Sci. U. S. A. 2008; 105: 3768-3773Crossref PubMed Scopus (153) Google Scholar,85.Kile A.C. et al.HLTF's ancient HIRAN domain binds 3' DNA ends to drive replication fork reversal.Mol. Cell. 2015; 58: 1090-1100Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar, 86.Blastyak A. et al.Role of double-stranded DNA translocase activity of human HLTF in replication of damaged DNA.Mol. Cell. 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Cell Biol. 2006; 175: 703-708Crossref PubMed Scopus (144) Google Scholar,59.Unk I. et al.Human SHPRH is a ubiquitin ligase for Mms2-Ubc13-dependent polyubiquitylation of proliferating cell nuclear antigen.Proc. Natl. Acad. Sci. U. S. A. 2006; 103: 18107-18112Crossref PubMed Scopus (156) Google Scholar]CRL2LRR1Ubiquitylates MCM7 to promote p97-dependent CMG unloading upon fork convergence during replication termination[27.Dewar J.M. et al.CRL2(Lrr1) promotes unloading of the vertebrate replisome from chromatin during replication termination.Genes Dev. 2017; 31: 275-290Crossref PubMed Scopus (45) Google Scholar,29.Sonneville R. et al.CUL-2(LRR-1) and UBXN-3 drive replisome disassembly during DNA replication termination and mitosis.Nat. Cell Biol. 2017; 19: 468-479Crossref PubMed Scopus (0) Google Scholar,101.Deegan T.D. et al.CMG helicase disassembly is controlled by replication fork DNA, replisome components and a ubiquitin threshold.eLife. 2020; 9e60371Crossref PubMed Google Scholar]FANCLComponent of the FA core complex that monoubiquitylates FANCD2 and FANCI in conjunction with the E2 enzyme UBE2T[11.Ceccaldi R. et al.The Fanconi anaemia pathway: new players and new functions.Nat. Rev. Mol. Cell Biol. 2016; 17: 337-349Crossref PubMed Scopus (299) Google Scholar,71.Rajendra E. et al.The genetic and biochemical basis of FANCD2 monoubiquitination.Mol. Cell. 2014; 54: 858-869Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar]RNF168Ubiquitylates H2A-type histones on K13 and K15 to promote recruitment of 53BP1, RNF169, and the BRCA1–A complex[15.Schwertman P. et al.Regulation of DNA double-strand break repair by ubiquitin and ubiquitin-like modifiers.Nat. Rev. Mol. Cell Biol. 2016; 17: 379-394Crossref PubMed Scopus (163) Google Scholar,98.Schmid J.A. et al.Histone ubiquitination by the DNA damage response is required for efficient DNA replication in unperturbed S phase.Mol. Cell. 2018; 71: 897-910.e8Abstract Full Text Full Text PDF PubMed Google Scholar]FBH1Accumulates at stalled forks and functions as a negative regulator of HR by disrupting RAD51 nucleofilaments[90.Bacquin A. et al.The helicase FBH1 is tightly regulated by PCNA via CRL4(Cdt2)-mediated proteolysis in human cells.Nucleic Acids Res. 2013; 41: 6501-6513Crossref PubMed Scopus (0) Google Scholar, 91.Fugger K. et al.Human Fbh1 helicase contributes to genome maintenance via pro- and anti-recombinase activities.J. Cell Biol. 2009; 186: 655-663Crossref PubMed Scopus (68) Google Scholar, 92.Chu W.K. et al.FBH1 influences DNA replication fork stability and homologous recombination through ubiquitylation of RAD51.Nat. Commun. 2015; 6: 5931Crossref PubMed Google Scholar, 93.Fugger K. et al.FBH1 catalyzes regression of stalled replication forks.Cell Rep. 2015; 10: 1749-1757Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar]PRP19Contributes to RPA ubiquitylation upon DNA damage[39.Marechal A. et al.PRP19 transforms into a sensor of RPA-ssDNA after DNA damage and drives ATR activation via a ubiquitin-mediated circuitry.Mol. Cell. 2014; 53: 235-246Abstract Full Text Full Text PDF PubMed Scopus (143) Google Scholar]ReadersY-family TLS polymerasesInteract with monoubiquitylated PCNA and enable error-prone replication past DNA lesions due to their flexible active sites[53.Choe K.N. Moldovan G.L. Forging ahead through darkness: PCNA, still the principal conductor at the replication fork.Mol. Cell. 2017; 65: 380-392Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar,54.Garcia-Rodriguez N. et al.Functions of ubiquitin and SUMO in DNA replication and replication stress.Front. Genet. 2016; 7: 87Crossref PubMed Scopus (0) Google Scholar]ZRANB3Translocase that recognizes K63-polyubiquitylated PCNA and promotes fork reversal[82.Vujanovic M. et al.Replication fork slowing and reversal upon DNA damage require PCNA polyubiquitination and ZRANB3 DNA translocase activity.Mol. Cell. 2017; 67: 882-890.e5Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar, 83.Ciccia A. et al.Polyubiquitinated PCNA recruits the ZRANB3 translocase to maintain genomic integrity after replication stress.Mol. Cell. 2012; 47: 396-409Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar, 84.Yuan J. et al.The HARP-like domain-containing protein AH2/ZRANB3 binds to PCNA and participates in cellular response to replication stress.Mol. Cell. 2012; 47: 410-421Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar]p97 and cofactors (UFD1-NPL4-FAF1)Recognize ubiquitylated client proteins to promote their displacement from replication forks[22.Franz A. et al.Ring of change: CDC48/p97 drives protein dynamics at chromatin.Front. Genet. 2016; 7: 73Crossref PubMed Scopus (47) Google Scholar, 23.Franz A. et al.Chromatin-associated degradation is defined by UBXN-3/FAF1 to safeguard DNA replication fork progression.Nat. Commun. 2016; 7: 10612Crossref PubMed Google Scholar, 24.Havens C.G. Walter J.C. Mechanism of CRL4(Cdt2), a PCNA-dependent E3 ubiquitin ligase.Genes Dev. 2011; 25: 1568-1582Crossref PubMed Scopus (154) Google Scholar, 25.Raman M. et al.A genome-wide screen identifies p97 as an essential regulator of DNA damage-dependent CDT1 destruction.Mol. Cell. 2011; 44: 72-84Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar, 26.Maric M. et al.Cdc48 and a ubiquitin ligase drive disassembly of the CMG helicase at the end of DNA replication.Science. 2014; 346: 1253596Crossref PubMed Scopus (120) Google Scholar, 27.Dewar J.M. et al.CRL2(Lrr1) promotes unloading of the vertebrate replisome from chromatin during replication termination.Genes Dev. 2017; 31: 275-290Crossref PubMed Scopus (45) Google Scholar, 28.Moreno S.P. et al.Polyubiquitylation drives replisome disassembly at the termination of DNA replication.Science. 2014; 346: 477-481Crossref PubMed Scopus (106) Google Scholar, 29.Sonneville R. et al.CUL-2(LRR-1) and UBXN-3 drive replisome disassembly during DNA replication termination and mitosis.Nat. Cell Biol. 2017; 19: 468-479Crossref PubMed Scopus (0) Google Scholar, 30.Wu R.A. et al.TRAIP is a master regulator of DNA interstrand crosslink repair.Nature. 2019; 567: 267-272Crossref PubMed Scopus (48) Google Scholar,42.Inano S. et al.RFWD3-mediated ubiquitination promotes timely removal of both RPA and RAD51 from DNA damage sites to facilitate homologous recombination.Mol. Cell. 2017; 66: 622-634.e8Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar]WRNIPAccumulates at stalled forks via binding to ubiquitylated PCNA and stabilizes RAD51 nucleofilaments[94.Crosetto N. et al.Human Wrnip1 is localized in replication factories in a ubiquitin-binding zinc finger-dependent manner.J. Biol. 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Cell. 2016; 64: 688-703Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar, 63.Vaz B. et al.Metalloprotease SPRTN/DVC1 orchestrates replication-coupled DNA-protein crosslink repair.Mol. Cell. 2016; 64: 704-719Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar]26S proteasomeRecognizes and proteolytically degrades ubiquitylated DPCs[61.Larsen N.B. et al.Replication-coupled DNA-protein crosslink repair by SPRTN and the proteasome in Xenopus Egg Extracts.Mol. Cell. 2019; 73: 574-588.e7Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar]53BP1Reader of RNF168-dependent H2A(X) ubiquitylation that protects stalled or reversed forks from nucleolytic degradation by MRE11[97.Her J. et al.53BP1 Mediates ATR-Chk1 signaling and protects replication forks under conditions of replication stress.Mol. Cell. Biol. 2018; 38: e00472-e00517Crossref PubMed Scopus (24) Google Scholar, 98.Schmid J.A. et al.Histone ubiquitination by the DNA damage response is required for efficient DNA replication in unperturbed S phase.Mol. Cell. 2018; 71: 897-910.e8Abstract Full Text Full Text PDF PubMed Google Scholar, 99.Liu W. et al.Two replication fork remodeling pathways generate nuclease substrates for distinct fork protection factors.Sci. Adv. 2020; 6eabc3598Crossref PubMed Scopus (0) Google Scholar]NEIL3Glycosylase that recognizes short ubiquitin chains on CMG and directly cleaves ICLs[30.Wu R.A. et al.TRAIP is a master regulator of DNA interstrand crosslink repair.Nature. 2019; 567: 267-272Crossref PubMed Scopus (48) Google Scholar,108.Semlow D.R. et al.Replication-dependent unhooking of DNA interstrand cross-links by the NEIL3 Glycosylase.Cell. 2016; 167: 498-511.e14Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar]ErasersUSP7Deubiquitylates SUMOylated proteins at unstressed forks to prevent their displacement from the replisome. Deubiquitylates SPRTN[21.Lecona E. et al.USP7 is a SUMO deubiquitinase essential for DNA replication.Nat. Struct. Mol. 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