Abstract
Proliferating cell nuclear antigen (PCNA) and replication factor C (RFC) were identified in the late 1980s as essential factors for replication of simian virus 40 DNA in human cells, by reconstitution of the reaction in vitro. Initially, they were only thought to be involved in the elongation stage of DNA replication. Subsequent studies have demonstrated that PCNA functions as more than a replication factor, through its involvement in multiple protein-protein interactions. PCNA appears as a functional hub on replicating and replicated chromosomal DNA and has an essential role in the maintenance genome integrity in proliferating cells.
Eukaryotes have multiple paralogues of sliding clamp, PCNA and its loader, RFC. The PCNA paralogues, RAD9, HUS1, and RAD1 form the heterotrimeric 9-1-1 ring that is similar to the PCNA homotrimeric ring, and the 9-1-1 clamp complex is loaded onto sites of DNA damage by its specific loader RAD17-RFC. This alternative clamp-loader system transmits DNA-damage signals in genomic DNA to the checkpoint-activation network and the DNA-repair apparatus.
Another two alternative loader complexes, CTF18-RFC and ELG1-RFC, have roles that are distinguishable from the role of the canonical loader, RFC. CTF18-RFC interacts with one of the replicative DNA polymerases, PolĪµ, and loads PCNA onto leading-strand DNA, and ELG1-RFC unloads PCNA after ligation of lagging-strand DNA. In the progression of S phase, these alternative PCNA loaders maintain appropriate amounts of PCNA on the replicating sister DNAs to ensure that specific enzymes are tethered at specific chromosomal locations.
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References
Abbas T, Sivaprasad U, Terai K, Amador V, Pagano M, Dutta A (2008) PCNA-dependent regulation of p21 ubiquitylation and degradation via the CRL4Cdt2 ubiquitin ligase complex. Genes Dev 22:2496ā2506
Abbas T, Shibata E, Park J, Jha S, Karnani N, Dutta A (2010) CRL4 Cdt2 regulates cell proliferation and histone gene expression by targeting PR-Set7/Set8 for degradation. Mol Cell 40:9ā21
Acevedo J, Yan S, Michael WM (2016) Direct binding to replication protein a (RPA)-coated single-stranded DNA allows recruitment of the ATR activator TopBP1 to sites of DNA damage. J Biol Chem 291:13124ā13131
Alabert C, Bukowski-Wills JC, Lee SB, Kustatscher G, Nakamura K, de Lima AF, Menard P, Mejlvang J, Rappsilber J, Groth A (2014) Nascent chromatin capture proteomics determines chromatin dynamics during DNA replication and identifies unknown fork components. Nat Cell Biol 16:281ā293
Arias EE, Walter JC (2005) Replication-dependent destruction of Cdt1 limits DNA replication to a single round per cell cycle in Xenopus egg extracts. Genes Dev 19:114ā126
Awasthi P, Foiani M, Kumar A (2015) ATM and ATR signaling at a glance. J Cell Sci 128:4255ā4262
Aylon Y, Kupiec M (2003) The checkpoint protein Rad24 of saccharomyces cerevisiae is involved in processing double-strand break ends and in recombination partner choice. Mol Cell Biol 23(18):6585ā6596
Balakrishnan L, Brandt PD, Lindsey-Boltz LA, Sancar A, Bambara RA (2009) Long patch base excision repair proceeds via coordinated stimulation of the multienzyme DNA repair complex. J Biol Chem 284:15158ā15172
Bao S, Tibbetts RS, Brumbaugh KM, Fang Y, Richardson DA, Ali A, Chen SM, Abraham RT, Wang XF (2001) ATR/ATM-mediated phosphorylation of human Rad17 is required for genotoxic stress responses. Nature 411:969ā974
Bermudez VP, Lindsey-Boltz LA, Cesare AJ, Maniwa Y, Griffith JD, Hurwitz J, Sancar A (2003) Loading of the human 9-1-1 checkpoint complex onto DNA by the checkpoint clamp loader hRad17-replication factor C complex in vitro. Proc Natl Acad Sci U S A 100:1633ā1638
Bienko M, Green CM, Crosetto N, Rudolf F, Zapart G, Coull B, Kannouche P, Wider G, Peter M, Lehmann AR, Hofmann K, Dikic I (2005) Ubiquitin-binding domains in Y-family polymerases regulate translesion synthesis. Science 310:1821ā1824
Boehm EM, Washington MT (2016) R.I.P. to the PIP: PCNA-binding motif no longer considered specific: PIP motifs and other related sequences are not distinct entities and can bind multiple proteins involved in genome maintenance. BioEssays 38:1117ā1122
Burgers PM (2009) Polymerase dynamics at the eukaryotic DNA replication fork. J Biol Chem 284:4041ā4055
Burtelow MA, Kaufmann SH, Karnitz LM (2000) Retention of the human Rad9 checkpoint complex in extraction-resistant nuclear complexes after DNA damage. J Biol Chem 275:26343ā26348
Burtelow MA, Roos-Mattjus PM, Rauen M, Babendure JR, Karnitz LM (2001) Reconstitution and molecular analysis of the hRad9-hHus1-hRad1 (9-1-1) DNA damage responsive checkpoint complex. J Biol Chem 276:25903ā25909
Bylund GO, Burgers PM (2005) Replication protein A-directed unloading of PCNA by the Ctf18 cohesion establishment complex. Mol Cell Biol 25:5445ā5455
Byun TS, Pacek M, Yee MC, Walter JC, Cimprich KA (2005) Functional uncoupling of MCM helicase and DNA polymerase activities activates the ATR-dependent checkpoint. Genes Dev 19:1040ā1052
Carr AM, Lambert S (2013) Replication stress-induced genome instability: the dark side of replication maintenance by homologous recombination. J Mol Biol 425:4733ā4744
Caspari T, Dahlen M, Kanter-Smoler G, Lindsay HD, Hofmann K, Papadimitriou K, Sunnerhagen P, Carr AM (2000) Characterization of Schizosaccharomyces pombe Hus1: a PCNA-related protein that associates with Rad1 and Rad9. Mol Cell Biol 74:1254ā1262
Chen MJ, Lin YT, Lieberman HB, Chen G, Lee EY (2001) ATM-dependent phosphorylation of human Rad9 is required for ionizing radiation-induced checkpoint activation. J Biol Chem 276:16580ā16586
Chen X, Paudyal SC, Chin RI, You Z (2013) PCNA promotes processive DNA end resection by Exo1. Nucleic Acids Res 41:9325ā9338
Choe KN, Moldovan GL (2017) Forging ahead through darkness: PCNA, still the principal conductor at the replication fork. Mol Cell 65:380ā392
Chuang LC, Yew PR (2001) Regulation of nuclear transport and degradation of the Xenopus cyclin-dependent kinase inhibitor, p27Xic1. J Biol Chem 276:1610ā1617
Chuang LS, Ian HI, Koh TW, Ng HH, Xu G, Li BF (1997) Human DNA-(cytosine-5) methyltransferase-PCNA complex as a target for p21WAF1. Science 277:1996ā2000
Cimprich KA, Cortez D (2008) ATR: an essential regulator of genome integrity. Nat Rev Mol Cell Biol 9:616ā627
Cotta-Ramusino C, McDonald ER 3rd, Hurov K, Sowa ME, Harper JW, Elledge SJ (2011) A DNA damage response screen identifies RHINO, a 9-1-1 and TopBP1 interacting protein required for ATR signaling. Science 332:1313ā1317
CrabbĆ© L, Thomas A, Pantesco V, De Vos J, Pasero P, Lengronne A (2010) Analysis of replication profiles reveals key role of RFCāCtf18 in yeast replication stress response. Nat Struct Mol Biol 17:1391ā1397
De March M, Merino N, Barrera-Vilarmau S, Crehuet R, Onesti S, Blanco FJ, De Biasio A (2017) Structural basis of human PCNA sliding on DNA. Nat Commun 8:13935
Delacroix S, Wagner JM, Kobayashi M, Yamamoto K, Karnitz LM (2007) The Rad9-Hus1-Rad1 (9-1-1) clamp activates checkpoint signaling via TopBP1. Genes Dev 21:1472ā1477
Dianov GL, Sleeth KM, Dianova II, Allinson SL (2003) Repair of abasic sites in DNA. Mutat Res 531:157ā163
DorĆ© AS, Kilkenny ML, Rzechorzek NJ, Pearl LH (2009) Crystal structure of the rad9-rad1-hus1 DNA damage checkpoint complex--implications for clamp loading and regulation. Mol Cell 34:735ā745
Dua R, Levy DL, Campbell JL (1999) Analysis of the essential functions of the C-terminal protein/protein interaction domain of Saccharomyces cerevisiae pol Īµ and its unexpected ability to support growth in the absence of the DNA polymerase domain. J Biol Chem 274:22283ā22288
Duursma AM, Driscoll R, Elias JE, Cimprich KA (2013) A role for the MRN complex in ATR activation via TOPBP1 recruitment. Mol Cell 50:116ā122
Edmunds CE, Simpson LJ, Sale JE (2008) PCNA ubiquitination and REV1 define temporally distinct mechanisms for controlling translesion synthesis in the avian cell line DT40. Mol Cell 30:519ā529
Ellison V, Stillman B (2003) Biochemical characterization of DNA damage checkpoint complexes: clamp loader and clamp complexes with specificity for 5ā² recessed DNA. PLoS Biol 1:e33
Fan J, Otterlei M, Wong HK, Tomkinson AE, Wilson DM 3rd (2004) XRCC1 co-localizes and physically interacts with PCNA. Nucleic Acids Res 32:2193ā2201
Feng W, DāUrso G (2001) Schizosaccharomyces pombe cells lacking the amino-terminal catalytic domains of DNA polymerase Īµ are viable but require the DNA damage checkpoint control. Mol Cell Biol 21:4495ā4504
Flores-Rozas H, Clark D, Kolodner RD (2000) Proliferating cell nuclear antigen and Msh2p-Msh6p interact to form an active mispair recognition complex. Nat Genet 26:375ā378
Fridman Y, Gur E, Fleishman SJ, Aharoni A (2013) Computational protein design suggests that human PCNA-partner interactions are not optimized for affinity. Proteins 81:341ā348
Fujisawa R, Ohashi E, Hirota K, Tsurimoto T (2017) Human CTF18-RFC clamp-loader complexed with non-synthesising DNA polymerase Īµ efficiently loads the PCNA sliding clamp. Nucleic Acids Res 45(8):4550ā4563
Furuya K, Poitelea M, Guo L, Caspari T, Carr AM (2004) Chk1 activation requires Rad9 S/TQ-site phosphorylation to promote association with C-terminal BRCT domains of Rad4TOPBP1. Genes Dev 18:1154ā1164
Gali H, Juhasz S, Morocz M, Hajdu I, Fatyol K, Szukacsov V, Burkovics P, Haracska L (2012) Role of SUMO modification of human PCNA at stalled replication fork. Nucleic Acids Res 40:6049ā6059
GarcĆa-RodrĆguez LJ, De Piccoli G, Marchesi V, Jones RC, Edmondson RD, Labib K (2015) A conserved PolĻµ binding module in Ctf18-RFC is required for S-phase checkpoint activation downstream of Mec1. Nucleic Acids Res 43:8830ā8838
Gary R, Ludwig DL, Cornelius HL, MacInnes MA, Park MS (1997) The DNA repair endonuclease XPG binds to proliferating cell nuclear antigen (PCNA) and shares sequence elements with the PCNA-binding regions of FEN-1 and cyclin-dependent kinase inhibitor p21. J Biol Chem 272:24522ā24529
Gembka A, Toueille M, Smirnova E, Poltz R, Ferrari E, Villani G, HĆ¼bscher U (2007) The checkpoint clamp, Rad9-Rad1-Hus1 complex, preferentially stimulates the activity of apurinic/apyrimidinic endonuclease 1 and DNA polymerase beta in long patch base excision repair. Nucleic Acids Res 35:2596ā2608
Georgescu RE, Langston L, Yao NY, Yurieva O, Zhang D, Finkelstein J, Agarwal T, OāDonnell ME (2014) Mechanism of asymmetric polymerase assembly at the eukaryotic replication fork. Nat Struct Mol Biol 21:664ā670
Georgescu RE, Schauer GD, Yao NY, Langston LD, Yurieva O, Zhang D, Finkelstein J, OāDonnell ME (2015a) Reconstitution of a eukaryotic replisome reveals suppression mechanisms that define leading/lagging strand operation. Elife 4:e04988
Georgescu R, Langston L, OāDonnell M (2015b) A proposal: evolution of PCNAās role as a marker of newly replicated DNA. DNA Repair (Amst) 29:4ā15
Goellner EM, Smith CE, Campbell CS, Hombauer H, Desai A, Putnam CD, Kolodner RD (2014) PCNA and Msh2-Msh6 activate an Mlh1-Pms1 endonuclease pathway required for Exo1-independent mismatch repair. Mol Cell 55:291ā304
Gong Z, Kim JE, Leung CC, Glover JN, Chen J (2010) BACH1/FANCJ acts with TopBP1 and participates early in DNA replication checkpoint control. Mol Cell 37:438ā446
Greer DA, Besley BD, Kennedy KB, Davey S (2003) hRad9 rapidly binds DNA containing double-strand breaks and is required for damage-dependent topoisomerase II beta binding protein 1 focus formation. Cancer Res 63:4829ā4835
Griffith JD, Lindsey-Boltz LA, Sancar A (2002) Structures of the human Rad17-replication factor C and checkpoint Rad 9-1-1 complexes visualized by glycerol spray/low voltage microscopy. J Biol Chem 277:15233ā15236
Grushcow JM, Holzen TM, Park KJ, Weinert T, Lichten M, Bishop DK (1999) Saccharomyces cerevisiae checkpoint genes MEC1, RAD17 and RAD24 are required for normal meiotic recombination partner choice. Genetics 153:607ā620
Guo C, Tang TS, Bienko M, Parker JL, Bielen AB, Sonoda E, Takeda S, Ulrich HD, Dikic I, Friedberg EC (2006) Ubiquitin-binding motifs in REV1 protein are required for its role in the tolerance of DNA damage. Mol Cell Biol 26:8892ā8900
Hanna JS, Kroll ES, Lundblad V, Spencer FA (2001) Saccharomyces cerevisiae CTF18 and CTF4 are required for sister chromatid cohesion. Mol Cell Biol 21:3144ā3158
Havens CG, Walter JC (2009) Docking of a specialized PIP box onto chromatin-bound PCNA creates a Degron for the ubiquitin ligase CRL4Cdt2. Mol Cell 35:93ā104
Henneke G, Koundrioukoff S, Hubscher U (2003) Phosphorylation of human Fen1 by cyclin-dependent kinase modulates its role in replication fork regulation. Oncogene 22:4301ā4313
Hochwagen A, Amon A (2006) Checking your breaks: surveillance mechanisms of meiotic recombination. Curr Biol 16:R217āR228
Hoege C, Pfander B, Moldovan GL, Pyrowolakis G, Jentsch S (2002) RAD6-dependent DNA repair is linked to modification of PCNA by ubiquitin and SUMO. Nature 419:135ā141
Hofmann JFX, Beach D (1994) cdt1 is an essential target of the Cdc10/Sct1 transcription factor: requirement for DNA replication and inhibition of mitosis. EMBO J 13:425ā434
Huang TT, Nijman SM, Mirchandani KD, Galardy PJ, Cohn MA, Haas W, Gygi SP, Ploegh HL, Bernards R, DāAndrea AD (2006) Regulation of monoubiquitinated PCNA by DUB autocleavage. Nat Cell Biol 8:339ā347
Iida T, Suetake I, Tajima S, Morioka H, Ohta S, Obuse C, Tsurimoto T (2002) PCNA clamp facilitates action of DNA cytosine methyltransferase 1 on hemimethylated DNA. Genes Cells 7:997ā1007
Indiani C, OāDonnell M (2006) The replication clamp-loading machine at work in the three domains of life. Nat Rev Mol Cell Biol 7:751ā761
Indiani C, McInerney P, Georgescu R, Goodman MF, Oā²Donnell M. (2005) A sliding-clamp tool belt binds high- and low-fidelity DNA polymerases simultaneously. Mol Cell 19:805ā815
Iyer RR, Pluciennik A, Burdett V, Modrich PL (2006) DNA mismatch repair: functions and mechanisms. Chem Rev 106:302ā323
Johnson C, Gali VK, Takahashi TS, Kubota T (2016) PCNA retention on DNA into G2/M phase causes genome instability in cells lacking Elg1. Cell Rep 16:684ā695
Kadyrov FA, Dzantiev L, Constantin N, Modrich P (2006) Endonucleolytic function of MutLalpha in human mismatch repair. Cell 126:297ā308
Kadyrov FA, Holmes SF, Arana ME, Lukianova OA, OāDonnell M, Kunkel TA, Modrich P (2007) Saccharomyces cerevisiae MutLalpha is a mismatch repair endonuclease. J Biol Chem 282:37181ā37190
Kai M, Wang TS (2003) Checkpoint activation regulates mutagenic translesion synthesis. Genes Dev 17:64ā76
Kai M, Furuya K, Paderi F, Carr AM, Wang TS (2007) Rad3-dependent phosphorylation of the checkpoint clamp regulates repair-pathway choice. Nat Cell Biol 9:691ā697
Karras GI, Fumasoni M, Sienski G, Vanoli F, Branzei D, Jentsch S (2013) Noncanonical role of the 9-1-1 clamp in the error-free DNA damage tolerance pathway. Mol Cell 49:536ā546
Kaur R, Kostrub CF, Enoch T (2001) Structure-function analysis of fission yeast Hus1-Rad1-Rad9 checkpoint complex. Mol Biol Cell 12:3744ā3758
Kawasoe Y, Tsurimoto T, Nakagawa T, Masukata H, Takahashi TS (2016) MutSa maintains the mismatch repair capability by inhibiting PCNA unloading. Elife 5:e15155
Kedar PS, Kim SJ, Robertson A, Hou E, Prasad R, Horton JK, Wilson SH (2002) Direct interaction between mammalian DNA polymerase beta and proliferating cell nuclear antigen. J Biol Chem 277:31115ā311123
Kelch BA, Makino DL, OāDonnell M, Kuriyan J (2012) Clamp loader ATPases and the evolution of DNA replication machinery. BMC Biol 10:34
Kesti T, Flick K, Keranen S, Syvaoja JE, Wittenberg C (1999) DNA polymerase Īµ catalytic domains are dispensable for DNA replication, DNA repair, and cell viability. Mol Cell 3:679ā685
Kim BJ, Lee H (2008) Lys-110 is essential for targeting PCNA to replication and repair foci, and the K110A mutant activates apoptosis. Biol Cell 100:675ā686
Kim J, MacNeill SA (2003) Genome stability: a new member of the RFC family. Curr Biol 13:R873āR875
Kim SH, Michael WM (2008) Regulated proteolysis of DNA polymerase eta during the DNA-damage response in C. Elegans. Mol Cell 32:757ā766
Kim ST, Lim DS, Canman CE, Kastan MB (1999) Substrate specificities and identification of putative substrates of ATM kinase family members. J Biol Chem 274:37538ā37543
Kim Y, Starostina NG, Kipreos ET (2008) The CRL4Cdt2 ubiquitin ligase targets the degradation of p21Cip1 to control replication licensing. Genes Dev 22:2507ā2519
Kleczkowska HE, Marra G, Lettieri T, Jiricny J (2001) hMSH3 and hMSH6 interact with PCNA and colocalize with it to replication foci. Genes Dev 15:724ā736
Kobayashi M, Hirano A, Kumano T, Xiang SL, Mihara K, Haseda Y, Matsui O, Shimizu H, Yamamoto K (2004) Critical role for chicken Rad17 and Rad9 in the cellular response to DNA damage and stalled DNA replication. Genes Cells 9:291ā303
Kochaniak AB, Habuchi S, Loparo JJ, Chang DJ, Cimprich KA, Walter JC, van Oijen AM (2009) Proliferating cell nuclear antigen uses two distinct modes to move along DNA. J Biol Chem 284:17700ā117710
Kondo T, Matsumoto K, Sugimoto K (1999) Role of a complex containing Rad17, Mec3, and Ddc1 in the yeast DNA damage checkpoint pathway. Mol Cell Biol 19:1136ā1143
Kondo T, Wakayama T, Naiki T, Matsumoto K, Sugimoto K (2001) Recruitment of Mec1 and Ddc1 checkpoint proteins to double-strand breaks through distinct mechanisms. Science 294:867ā870
Koundrioukoff S, JĆ³nsson ZO, Hasan S, de Jong RN, van der Vliet PC, Hottiger MO, HĆ¼bscher U (2000) A direct interaction between proliferating cell nuclear antigen (PCNA) and Cdk2 targets PCNA-interacting proteins for phosphorylation. J Biol Chem 275:22882ā22887
Krokan HE, BjĆørĆ„s M (2013) Base excision repair. Cold Spring Harb Perspect Biol 5:a012583
Kubota T, Nishimura K, Kanemaki MT, Donaldson AD (2013a) The Elg1 replication factor C-like complex functions in PCNA unloading during DNA replication. Mol Cell 50:273ā280
Kubota T, Myung K, Donaldson AD (2013b) Is PCNA unloading the central function of the Elg1/ATAD5 replication factor C-like complex? Cell Cycle 12:2570ā2579
Kubota T, Katou Y, Nakato R, Shirahige K, Donaldson AD (2015) Replication-coupled PCNA unloading by the Elg1 complex occurs genome-wide and requires Okazaki fragment ligation. Cell Rep 12:774ā787
Kumagai A, Lee J, Yoo HY, Dunphy WG (2006) TopBP1 activates the ATR-ATRIP complex. Cell 124:943ā955
Kunkel TA, Erie DA (2005) DNA mismatch repair. Annu Rev Biochem 74:681ā710
Lavin MF (2008) Ataxia-telangiectasia: from a rare disorder to a paradigm for cell signalling and cancer. Nat Rev Mol Cell Biol 9:759ā769
Lee J, Dunphy WG (2013) The Mre11-Rad50-Nbs1 (MRN) complex has a specific role in the activation of Chk1 in response to stalled replication forks. Mol Biol Cell 24:1343ā1353
Lee J, Kumagai A, Dunphy WG (2003a) Claspin, a Chk1-regulatory protein, monitors DNA replication on chromatin independently of RPA, ATR, and Rad17. Mol Cell 11:329ā340
Lee J, Kumagai A, Dunphy WG (2007) The Rad9-Hus1-Rad1 checkpoint clamp regulates interaction of TopBP1 with ATR. J Biol Chem 282:28036ā28044
Lee KY, Fu H, Aladjem MI, Myung K (2013) ATAD5 regulates the lifespan of DNA replication factories by modulating PCNA level on the chromatin. J Cell Biol 200:31ā44
Lengronne A, McIntyre J, Katou Y, Kanoh Y, Hopfner KP, Shirahige K, Uhlmann F (2006) Establishment of sister chromatid cohesion at the S. Cerevisiae replication fork. Mol Cell 23:787ā799
Leonhardt H, Rahn HP, Weinzierl P, Sporbert A, Cremer T, Zink D, Cardoso MC (2000) Dynamics of DNA replication factories in living cells. J Cell Biol 149:271ā280
Li Z, Pearlman AH, Hsieh P (2016) DNA mismatch repair and the DNA damage response. DNA Repair (Amst) 38:94ā101
Lindsey-Boltz LA, Bermudez VP, Hurwitz J, Sancar A (2001) Purification and characterization of human DNA damage checkpoint Rad complexes. Proc Natl Acad Sci U S A 98:11236ā11241
Lindsey-Boltz LA, Kemp MG, Capp C, Sancar A (2015) RHINO forms a stoichiometric complex with the 9-1-1 checkpoint clamp and mediates ATR-Chk1 signaling. Cell Cycle 14:99ā108
Longhese MP, Paciotti V, Fraschini R, Zaccarini R, Plevani P, Lucchini G (1997) The novel DNA damage checkpoint protein ddc1p is phosphorylated periodically during the cell cycle and in response to DNA damage in budding yeast. EMBO J 16:5216ā5226
LĆ³pez de Saro FJ, OāDonnell M (2001) Interaction of the beta sliding clamp with MutS, ligase, and DNA polymerase I. Proc Natl Acad Sci U S A 98:8376ā8380
Lydall D, Nikolsky Y, Bishop DK, Weinert T (1996) A meiotic recombination checkpoint controlled by mitotic checkpoint genes. Nature 383:840ā843
Maga G, HĆ¼bscher U (2003) Proliferating cell nuclear antigen (PCNA): a dancer with many partners. J Cell Sci 116:3051ā3060
Mailand N, Gibbs-Seymour I, Bekker-Jensen S (2013) Regulation of PCNA-protein interactions for genome stability. Nat Rev Mol Cell Biol 14:269ā282
Majka J, Burgers PM (2004) The PCNA-RFC families of DNA clamps and clamp loaders. Prog Nucleic Acid Res Mol Biol 78:227ā260
Majka J, Binz SK, Wold MS, Burgers PM (2006) Replication protein a directs loading of the DNA damage checkpoint clamp to 5ā²-DNA junctions. J Biol Chem 281:27855ā27861
MarƩchal A, Zou L (2013) DNA damage sensing by the ATM and ATR kinases. Cold Spring Harb Perspect Biol 5:a012716
Marsischky GT, Filosi N, Kane MF, Kolodner R (1996) Redundancy of Saccharomyces cerevisiae MSH3 and MSH6 in MSH2-dependent mismatch repair. Genes Dev 10:407ā420
Masuda Y, Piao J, Kamiya K (2010) DNA replication-coupled PCNA mono-ubiquitination and polymerase switching in a human in vitro system. J Mol Biol 396:487ā500
Matsuoka S, Ballif BA, Smogorzewska A, McDonald ER, Hurov KE, Luo J, Bakalarski CE, Zhao Z, Solimini N, Lerenthal Y, Shiloh Y, Gygi SP, Elledge SJ (2007) ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage. Science 316(5828):1160ā1166
Mayer ML, Gygi SP, Aebersold R, Hieter P (2001) Identification of RFC(Ctf18p, Ctf8p, Dcc1p): an alternative RFC complex required for sister chromatid cohesion in S. Cerevisiae. Mol Cell 7:959ā970
McInerney P, Johnson A, Katz F, OāDonnell M (2007) Characterization of a triple DNA polymerase replisome. Mol Cell 27:527ā538
Melo JA, Cohen J, Toczyski DP (2001) Two checkpoint complexes are independently recruited to sites of DNA damage in vivo. Genes Dev 15:2809ā2821
Merkle CJ, Karnitz LM, Henry-SĆ”nchez JT, Chen J (2003) Cloning and characterization of hCTF18, hCTF8, and hDCC1. Human homologs of a Saccharomyces cerevisiae complex involved in sister chromatid cohesion establishment. J Biol Chem 278:30051ā30056
Moldovan GL, Pfander B, Jentsch S (2006) PCNA controls establishment of sister chromatid cohesion during S phase. Mol Cell 23:723ā732
Moldovan GL, Pfander B, Jentsch S (2007) PCNA, the maestro of the replication fork. Cell 129:665ā679
Moldovan GL, Dejsuphong D, Petalcorin MI, Hofmann K, Takeda S, Boulton SJ, DāAndrea AD (2012) Inhibition of homologous recombination by the PCNA-interacting protein PARI. Mol Cell 45:75ā86
Mordes DA, Glick GG, Zhao R, Cortez D (2008) TopBP1 activates ATR through ATRIP and a PIKK regulatory domain. Genes Dev 22:1478ā1489
Mortusewicz O, Schermelleh L, Walter J, Cardoso MC, Leonhardt H (2005) Recruitment of DNA methyltransferase I to DNA repair sites. Proc Natl Acad Sci U S A 102:8905ā8909
Murakami T, Takano R, Takeo S, Taniguchi R, Ogawa K, Ohashi E, Tsurimoto T (2010) Stable interaction between the human proliferating cell nuclear antigen loader complex Ctf18-replication factor C (RFC) and DNA polymerase Īµ is mediated by the cohesion-specific subunits, Ctf18, Dcc1, and Ctf8. J Biol Chem 285:34608ā34615
Naiki T, Kondo T, Nakada D, Matsumoto K, Sugimoto K (2001) Chl12 (Ctf18) forms a novel replication factor C-related complex and functions redundantly with Rad24 in the DNA replication checkpoint pathway. Mol Cell Biol 21:5838ā5845
Navadgi-Patil VM, Burgers PM (2008) Yeast DNA replication protein Dpb11 activates the Mec1/ATR checkpoint kinase. J Biol Chem 283:35853ā35859
Navadgi-Patil VM, Burgers PM (2009) The unstructured C-terminal tail of the 9-1-1 clamp subunit Ddc1 activates Mec1/ATR via two distinct mechanisms. Mol Cell 36:743ā753
Nishino K, Inoue E, Takada S, Abe T, Akita M, Yoshimura A, Tada S, Kobayashi M, Yamamoto K, Seki M, Enomoto T (2008) A novel role for Rad17 in homologous recombination. Genes Genet Syst 83:427ā431
Nishitani H, Sugimoto N, Roukos V, Nakanishi Y, Saijo M, Obuse C, Tsurimoto T, Nakayama KI, Nakayama K, Fujita M, Lygerou Z, Nishimoto T (2006) Two E3 ubiquitin ligases, SCF-Skp2 and DDB1-Cul4, target human Cdt1 for proteolysis. EMBO J 25:1126ā1136
Nishitani H, Shiomi Y, Iida H, Michishita M, Takami T, Tsurimoto T (2008) CDK inhibitor p21 is degraded by a proliferating cell nuclear antigen-coupled Cul4-DDB1Cdt2 pathway during S phase and after UV irradiation. J Biol Chem 283:29045ā29052
OāDonnell M, Li H (2016) The eukaryotic replisome goes under the microscope. Curr Biol 26:R247āR256
Ohashi E, Takeishi Y, Ueda S, Tsurimoto T (2014) Interaction between Rad9-Hus1-Rad1 and TopBP1 activates ATR-ATRIP and promotes TopBP1 recruitment to sites of UV-damage. DNA Repair (Amst) 21:1ā11
OāNeill T, Dwyer AJ, Ziv Y, Chan DW, Lees-Miller SP, Abraham RH, Lai JH, Hill D, Shiloh Y, Cantley LC, Rathbun GA (2000) Utilization of oriented peptide libraries to identify substrate motifs selected by ATM. J Biol Chem 275:22719ā22727
Pandita RK, Sharma GG, Laszlo A, Hopkins KM, Davey S, Chakhparonian M, Gupta A, Wellinger RJ, Zhang J, Powell SN, Roti Roti JL, Lieberman HB, Pandita TK (2006) Mammalian Rad9 plays a role in telomere stability, S- and G2-phase-specific cell survival, and homologous recombinational repair. Mol Cell Biol 26:1850ā1864
Park SY, Jeong MS, Han CW, Yu HS, Jang SB (2016) Structural and functional insight into proliferating cell nuclear antigen. J Microbiol Biotechnol 26:637ā647
Parnas O, Zipin-Roitman A, Pfander B, Liefshitz B, Mazor Y, Ben-Aroya S, Jentsch S, Kupiec M (2010) Elg1, an alternative subunit of the RFC clamp loader, preferentially interacts with SUMOylated PCNA. EMBO J 29:2611ā2622
Paulovich AG, Armour CD, Hartwell LH (1998) The Saccharomyces cerevisiae RAD9, RAD17, RAD24 and MEC3 genes are required for tolerating irreparable, ultraviolet-induced DNA damage. Genetics 150:75ā93
Pluciennik A, Dzantiev L, Iyer RR, Constantin N, Kadyrov FA, Modrich P (2010) PCNA function in the activation and strand direction of MutLĪ± endonuclease in mismatch repair. Proc Natl Acad Sci U S A 107:16066ā16071
Prelich G, Stillman B (1988) Coordinated leading and lagging strand synthesis during SV40 DNA replication in vitro requires PCNA. Cell 53:117ā126
Prelich G, Kostura M, Marshak DR, Mathews MB, Stillman B (1987) The cell-cycle regulated proliferating cell nuclear antigen is required for SV40 DNA replication in vitro. Nature 326:471ā475
Prindle MJ, Loeb LA (2012) DNA polymerase delta in DNA replication and genome maintenance. Environ Mol Mutagen 53:666ā682
Puddu F, Granata M, Di Nola L, Balestrini A, Piergiovanni G, Lazzaro F, Giannattasio M, Plevani P, Muzi-Falconi M (2008) Phosphorylation of the budding yeast 9-1-1 complex is required for Dpb11 function in the full activation of the UV-induced DNA damage checkpoint. Mol Cell Biol 28:4782ā4793
Pursell ZF, Isoz I, Lundstrƶm EB, Johansson E, Kunkel TA (2007) Yeast DNA polymerase epsilon participates in leading-strand DNA replication. Science 317:127ā130
Rappas M, Oliver AW, Pearl LH (2011) Structure and function of the Rad9-binding region of the DNA-damage checkpoint adaptor TopBP1. Nucleic Acids Res 39:313ā324
Roos-Mattjus P, Vroman BT, Burtelow MA, Rauen M, Eapen AK, Karnitz LM (2002) Genotoxin-induced Rad9-Hus1-Rad1 (9-1-1) chromatin association is an early checkpoint signaling event. J Biol Chem 277:43809ā43812
Roos-Mattjus P, Hopkins KM, Oestreich AJ, Vroman BT, Johnson KL, Naylor S, Lieberman HB, Karnitz LM (2003) Phosphorylation of human Rad9 is required for genotoxin-activated checkpoint signaling. J Biol Chem 278:24428ā24437
Rousseau D, Cannella D, Boulaire J, Fitzgerald P, Fotedar A, Fotedar R (1999) Growth inhibition by CDK-cyclin and PCNA binding domains of p21 occurs by distinct mechanisms and is regulated by ubiquitin-proteasome pathway. Oncogene 18:4313ā4325
Rudra S, Skibbens RV (2013) Cohesin codes - interpreting chromatin architecture and the many facets of cohesin function. J Cell Sci 126:31ā41
Sabbioneda S, Minesinger BK, Giannattasio M, Plevani P, Muzi-Falconi M, Jinks-Robertson S (2005) The 9-1-1 checkpoint clamp physically interacts with polzeta and is partially required for spontaneous polzeta-dependent mutagenesis in Saccharomyces cerevisiae. J Biol Chem 280:38657ā38665
Saberi A, Nakahara M, Sale JE, Kikuchi K, Arakawa H, Buerstedde JM, Yamamoto K, Takeda S, Sonoda E (2008) The 9-1-1 DNA clamp is required for immunoglobulin gene conversion. Mol Cell Biol 28:6113ā6122
Sancar A, Lindsey-Boltz LA, Unsal-KaƧmaz K, Linn S (2004) Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints. Annu Rev Biochem 73:39ā85
Shibahara K, Stillman B (1999) Replication-dependent marking of DNA by PCNA facilitates CAF-1-coupled inheritance of chromatin. Cell 96:575ā585
Shibutani ST, de la Cruz AF, Tran V, Turbyfill WJ 3rd, Reis T, Edgar BA, Duronio RJ (2008) Intrinsic negative cell cycle regulation provided by PIP box- and Cul4Cdt2-mediated destruction of E2f1 during S phase. Dev Cell 15:890ā900
Shinohara M, Sakai K, Ogawa T, Shinohara A (2003) The mitotic DNA damage checkpoint proteins Rad17 and Rad24 are required for repair of double-strand breaks during meiosis in yeast. Genetics 164:855ā865
Shiomi Y, Nishitani H (2013) Alternative replication factor C protein, Elg1, maintains chromosome stability by regulating PCNA levels on chromatin. Genes Cells 18:946ā959
Shiomi Y, Nishitani H (2017) Control of genome integrity by RFC complexes; conductors of PCNA loading onto and unloading from chromatin during DNA replication. Genes (Basel) 8., pii:E52
Shiomi Y, Shinozaki A, Nakada D, Sugimoto K, Usukura J, Obuse C, Tsurimoto T (2002) Clamp and clamp loader structures of the human checkpoint protein complexes, Rad9-1-1 and Rad17-RFC. Genes Cells 7:861ā868
Shiomi Y, Shinozaki A, Sugimoto K, Usukura J, Obuse C, Tsurimoto T (2004) The reconstituted human Chl12-RFC complex functions as a second PCNA loader. Genes Cells 9:279ā290
Shiomi Y, Hayashi A, Ishii T, Shinmyozu K, Nakayama J, Sugasawa K, Nishitani H (2012) Two different replication factor C proteins, Ctf18 and RFC1, separately control PCNA-CRL4Cdt2-mediated Cdt1 proteolysis during S phase and following UV irradiation. Mol Cell Biol 32:2279ā2288
Sirbu BM, McDonald WH, Dungrawala H, Badu-Nkansah A, Kavanaugh GM, Chen Y, Tabb DL, Cortez D (2013) Identification of proteins at active, stalled, and collapsed replication forks using isolation of proteins on nascent DNA (iPOND) coupled with mass spectrometry. J Biol Chem 288:31458ā31467
Skibbens RV (2009) Establishment of sister chromatid cohesion. Curr Biol 19:R1126āR1132
Smith LA, Makarova AV, Samson L, Thiesen KE, Dhar A, Bessho T (2012) Bypass of a psoralen DNA interstrand cross-link by DNA polymerases Ī², Ī¹, and Īŗ in vitro. Biochemistry 51:8931ā8938
St Onge RP, Udell CM, Casselman R, Davey S (1999) The human G2 checkpoint control protein hRAD9 is a nuclear phosphoprotein that forms complexes with hRAD1 and hHUS1. Mol Biol Cell 10:1985ā1995
St Onge RP, Besley BD, Park M, Casselman R, Davey S (2001) DNA damage-dependent and -independent phosphorylation of the hRad9 checkpoint protein. J Biol Chem 276:41898ā41905
St Onge RP, Besley BD, Pelley JL, Davey S (2003) A role for the phosphorylation of hRad9 in checkpoint signaling. J Biol Chem 278:26620ā26628
Stelter P, Ulrich HD (2003) Control of spontaneous and damage-induced mutagenesis by SUMO and ubiquitin conjugation. Nature 425:188ā191
Subramanian VV, Hochwagen A (2014) The meiotic checkpoint network: step-by-step through meiotic prophase. Cold Spring Harb Perspect Biol 6:a016675
Sun Q, Tsurimoto T, Juillard F, Li L, Li S, De LeĆ³n VE, Chen S, Kaye K (2014) Kaposiās sarcoma-associated herpesvirus LANA recruits the DNA polymerase clamp loader to mediate efficient replication and virus persistence. Proc Natl Acad Sci U S A 111:11816ā11821
Takeishi Y, Ohashi E, Ogawa K, Masai H, Obuse C, Tsurimoto T (2010) Casein kinase 2-dependent phosphorylation of human Rad9 mediates the interaction between human Rad9-Hus1-Rad1 complex and TopBP1. Genes Cells 15:761ā771
Takeishi Y, Iwaya-Omi R, Ohashi E, Tsurimoto T (2015) Intramolecular binding of the Rad9 C terminus in the checkpoint clamp Rad9-Hus1-Rad1 is closely linked with its DNA binding. J Biol Chem 290:19923ā19932
Terai K, Abbas T, Jazaeri AA, Dutta A (2010) CRL4(Cdt2) E3 ubiquitin ligase monoubiquitinates PCNA to promote translesion DNA synthesis. Mol Cell 37:143ā149
Terret ME, Sherwood R, Rahman S, Qin J, Jallepalli PV (2009) Cohesin acetylation speeds the replication fork. Nature 462:231ā234
Thompson DA, Stahl FW (1999) Genetic control of recombination partner preference in yeast meiosis. Isolation and characterization of mutants elevated for meiotic unequal sister-chromatid recombination. Genetics 153:621ā641
Tinker RL, Kassavetis GA, Geiduschek EP (1994) Detecting the ability of viral, bacterial and eukaryotic proteins to track along DNA. EMBO J 13:5330ā5337
Tsurimoto T (1999) PCNA binding proteins. Front Biosci 4:D849āD858
Tsurimoto T, Stillman B (1989) Purification of a cellular replication factor, RF-C, that is required for coordinated synthesis of leading and lagging strands during simian virus 40 DNA replication in vitro. Mol Cell Biol 9:609ā619
Ueda S, Takeishi Y, Ohashi E, Tsurimoto T (2012) Two serine phosphorylation sites in the C-terminus of Rad9 are critical for 9-1-1 binding to TopBP1 and activation of the DNA damage checkpoint response in HeLa cells. Genes Cells 17:807ā816
Ulrich HD (2013) New insights into replication clamp unloading. J Mol Biol 425:4727ā4732
Ulrich HD, Jentsch S (2000) Two RING finger proteins mediate cooperation between ubiquitinconjugating enzymes in DNA repair. EMBO J 19:3388ā3397
Volkmer E, Karnitz LM (1999) Human homologs of Schizosaccharomyces pombe rad1, hus1, and rad9 form a DNA damage-responsive protein complex. J Biol Chem 274:567ā570
Waga S, Stillman B (1998) The DNA replication fork in eukaryotic cells. Annu Rev Biochem 67:721ā751
Waga S, Hannon GJ, Beach D, Stillman B (1994) The p21 inhibitor of cyclin-dependent kinases controls DNA replication by interaction with PCNA. Nature 369:574ā578
Wang X, Zou L, Zheng H, Wei Q, Elledge SJ, Li L (2003) Genomic instability and endoreduplication triggered by RAD17 deletion. Genes Dev 17:965ā970
Wang X, Hu B, Weiss RS, Wang Y (2006) The effect of Hus1 on ionizing radiation sensitivity is associated with homologous recombination repair but is independent of nonhomologous end-joining. Oncogene 25:1980ā1983
Warbrick E, Lane DP, Glover DM, Cox LS (1995) A small peptide inhibitor of DNA replication defines the site of interaction between the cyclin-dependent kinase inhibitor p21waf1 and the proliferating cell nuclear antigen. Curr Biol 5:275ā282
Weiss RS, Matsuoka S, Elledge SJ, Leder P (2002) Hus1 acts upstream of chk1 in a mammalian DNA damage response pathway. Curr Biol 12:73ā77
Wu X, Shell SM, Zou Y (2005) Interaction and colocalization of Rad9/Rad1/Hus1 checkpoint complex with replication protein a in human cells. Oncogene 24:4728ā4735
Xiong Y, Hannon GJ, Zhang H, Casso D, Kobayashi R, Beach D (1993) p21 is a universal inhibitor of cyclin kinases. Nature 366:701ā704
Xu X, Vaithiyalingam S, Glick GG, Mordes DA, Chazin WJ, Cortez D (2008) The basic cleft of RPA70N binds multiple checkpoint proteins, including RAD9, to regulate ATR signaling. Mol Cell Biol 28:7345ā7353
Yan S, Michael WM (2009) TopBP1 and DNA polymerase-alpha directly recruit the 9-1-1 complex to stalled DNA replication forks. J Cell Biol 184:793ā804
Yao NY, OāDonnell M (2012) The RFC clamp loader: structure and function. Subcell Biochem 62:259ā279
Yao N, Turner J, Kelman Z, Stukenberg PT, Dean F, Shechter D, Pan ZQ, Hurwitz J, OāDonnell M (1996) Clamp loading, unloading and intrinsic stability of the PCNA, beta and gp45 sliding clamps of human, E. Coli and T4 replicases. Genes Cells 1:101ā113
You Z, Kong L, Newport J (2002) The role of single-stranded DNA and polymerase alpha in establishing the ATR, Hus1 DNA replication checkpoint. J Biol Chem 277:27088ā27093
Yu C, Gan H, Han J, Zhou ZX, Jia S, Chabes A, Farrugia G, Ordog T, Zhang Z (2014) Strand-specific analysis shows protein binding at replication forks and PCNA unloading from lagging strands when forks stall. Mol Cell 56:551ā563
Zamir L, Zaretsky M, Fridman Y, Ner-Gaon H, Rubin E, Aharoni A (2012) Tight coevolution of proliferating cell nuclear antigen (PCNA)-partner interaction networks in fungi leads to interspecies network incompatibility. Proc Natl Acad Sci U S A 109:E406āE414
Zhang H, Xiong Y, Beach D (1993) Proliferating cell nuclear antigen and p21 are components of multiple cell cycle kinase complexes. Mol Biol Cell 4:897ā906
Zhang Z, Shibahara K, Stillman B (2000) PCNA connects DNA replication to epigenetic inheritance in yeast. Nature 408:221ā225
Zou L, Cortez D, Elledge SJ (2002) Regulation of ATR substrate selection by Rad17-dependent loading of Rad9 complexes onto chromatin. Genes Dev 16:198ā208
Zou L, Liu D, Elledge SJ (2003) Replication protein A-mediated recruitment and activation of Rad17 complexes. Proc Natl Acad Sci U S A 100:13827ā11383
Acknowledgments
We would like to thank Dr. T. S. Takahashi (Kyushu University) for the comments on the manuscript. We apologize to those colleagues whose work is not cited because of space restrictions. This work is supported by Grants-in-aid for Scientific Research (KAKENHI) 25131714, 25440011, 26114714, and 16H04743.
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Ohashi, E., Tsurimoto, T. (2017). Functions of Multiple Clamp and Clamp-Loader Complexes in Eukaryotic DNA Replication. In: Masai, H., Foiani, M. (eds) DNA Replication. Advances in Experimental Medicine and Biology, vol 1042. Springer, Singapore. https://doi.org/10.1007/978-981-10-6955-0_7
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