Abstract
Since the original observations made in James German’s Laboratory that Bloom’s syndrome cells lacking BLM exhibit a decreased rate of both DNA chain elongation and maturation of replication intermediates, a large body of evidence has supported the idea that BLM, and other members of the RecQ helicase family to which BLM belongs, play important roles in DNA replication. More recent evidence indicates roles for RecQ helicases in what can broadly be defined as replication fork ‘repair’ processes when, for example, forks encounter lesions or adducts in the template, or when forks stall due to lack of nucleotide precursors. More specifically, several roles in repair of damaged forks via homologous recombination pathways have been proposed. RecQ helicases are generally only recruited to sites of DNA replication following fork stalling or disruption, and they do so in a checkpoint-dependent manner. There, in addition to repair functions, they aid the stabilisation of stalled replication complexes and seem to contribute to the generation and/or transduction of signals that enforce S-phase checkpoints. RecQ helicases also interact physically and functionally with several key players in DNA replication, including RPA, PCNA, FEN1 and DNA polymerase δ. In this paper, we review the evidence that RecQ helicases contribute to the impressively high level of fidelity with which genome duplication is effected.
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Ababou M, Dumaire V, Lecluse Y, Amor-Gueret M (2002) Bloom’s syndrome protein response to ultraviolet-C radiation and hydroxyurea-mediated DNA synthesis inhibition. Oncogene 21:2079–2088
Ayyagari R, Gomes XV, Gordenin DA, Burgers PMJ (2003) Okazaki fragment maturation in yeast - I. Distribution of functions between FEN1 AND DNA2. J Biol Chem 278:1618–1625
Bachrati CZ, Hickson ID (2003) RecQ helicases: suppressors of tumorigenesis and premature aging. Biochem J 374:577–606
Bachrati CZ, Borts RH, Hickson ID (2006) Mobile D-loops are a preferred substrate for the Bloom’s syndrome helicase. Nucleic Acids Res 34:2269–2279
Bae SH, Seo YS (2000) Characterization of the enzymatic properties of the yeast dna2 Helicase/endonuclease suggests a new model for Okazaki fragment processing. J Biol Chem 275:38022–38031
Bae SH, Bae KH, Kim JA, Seo YS (2001) RPA governs endonuclease switching during processing of Okazaki fragments in eukaryotes. Nature 412:456–461
Bae SH, Kim DW, Kim J, Kim JH, Kim DH, Kim HD, Kang HY, Seo YS (2002) Coupling of DNA helicase and endonuclease activities of yeast Dna2 facilitates Okazaki fragment processing. J Biol Chem 277:26632–26641
Balajee AS, Machwe A, May A, Gray MD, Oshima J, Martin GM, Nehlin JO, Brosh RM, Orren DK, Bohr VA (1999) The Werner syndrome protein is involved in RNA polymerase II transcription. Mol Biol Cell 10:2655–2668
Bartek J, Lukas C, Lukas J (2004) Checking on DNA damage in S phase. Nat Rev Mol Cell Biol 5:792–804
Bjergbaek L, Cobb JA, Tsai-Pflugfelder M, Gasser SM (2005) Mechanistically distinct roles for Sgs1p in checkpoint activation and replication fork maintenance. EMBO J 24:405–417
Blow JJ, Laskey RA (1986) Initiation of DNA replication in nuclei and purified DNA by a cell-free extract of Xenopus eggs. Cell 47:577–587
Bohr VA (2005) Deficient DNA repair in the human progeroid disorder, Werner syndrome. Mutat Res 577:252–259
Brosh RM, von Kobbe C, Sommers JA, Karmakar P, Opresko PL, Piotrowski J, Dianova I, Dianov GL, Bohr VA (2001) Werner syndrome protein interacts with human flap endonuclease 1 and stimulates its cleavage activity. EMBO J 20:5791–5801
Brosh RM, Driscoll HC, Dianov GL, Sommers JA (2002) Biochemical characterization of the WRN-FEN-1 functional interaction. Biochemistry (Mosc) 41:12204–12216
Budd ME, Campbell JL (1995) A yeast gene required for DNA replication encodes a protein with homology to DNA helicases. Proc Natl Acad Sci USA 92:7642–7646
Chakraverty RK, Kearsey JM, Oakley TJ, Grenon M, de La Torre Ruiz MA, Lowndes NF, Hickson ID (2001) Topoisomerase III acts upstream of rad53p in the s-phase dna damage checkpoint. Mol Cell Biol 21:7150–62
Chang M, Bellaoui M, Zhang C, Desai R, Morozov P, Delgado-Cruzata L, Rothstein R, Freyer GA, Boone C, Brown GW (2005) RMI1/NCE4, a suppressor of genome instability, encodes a member of the RecQ helicase/Topo III complex. EMBO J 24:2024–2033
Chen CY, Graham J, Yan H (2001) Evidence for a replication function of FFA-1, the Xenopus orthologue of Werner syndrome protein. J Cell Biol 152:985–996
Cheok CF, Wu L, Garcia PL, Janscak P, Hickson ID (2005) The Bloom’s syndrome helicase promotes the annealing of complementary single-stranded DNA. Nucleic Acids Res 33:3932–3941
Choudhary S, Doherty KM, Handy CJ, Sayer JM, Yagi H, Jerina DM, Brosh RM (2006) Inhibition of Werner syndrome helicase activity by Benzo[a]pyrene diol epoxide adducts can be overcome by replication protein A. J Biol Chem 281:6000–6009
Chow KH, Courcelle J (2004) RecO acts with RecF and RecR to protect and maintain replication forks blocked by UV-induced DNA damage in Escherichia coli. J Biol Chem 279:3492–3496
Cobb JA, Bjergbaek L, Gasser SM (2002) RecQ helicases: at the heart of genetic stability. FEBS Lett 529:43–48
Cobb JA, Bjergbaek L, Shimada K, Frei C, Gasser SM (2003) DNA polymerase stabilization at stalled replication forks requires Mec1 and the RecQ helicase Sgs1. EMBO J 22:4325–4336
Cobb JA, Schleker T, Rojas V, Bjergbaek L, Tercero JA, Gasser SM (2005) Replisome instability, fork collapse, and gross chromosomal rearrangements arise synergistically from Mec1 kinase and RecQ helicase mutations. Genes Dev 19:3055–3069
Constantinou A, Tarsounas M, Karow JK, Brosh RM, Bohr VA, Hickson ID, West SC (2000) Werner’s syndrome protein (WRN) migrates Holliday junctions and co- localizes with RPA upon replication arrest. EMBO Rep 1:80–84
Courcelle J, Hanawalt PC (1999) RecQ and RecJ process blocked replication forks prior to the resumption of replication in UV-irradiated Escherichia coli. Mol Gen Genet 262:543–551
Courcelle J, Carswell-Crumpton C, Hanawalt PC (1997) recF and recR are required for the resumption of replication at DNA replication forks in Escherichia coli. Proc Natl Acad Sci USA 94:3714–3719
Courcelle J, Donaldson JR, Chow KH, Courcelle CT (2003) DNA damage-induced replication fork regression and processing in Escherichia coli. Science 299:1064–1067
Courcelle CT, Chow KH, Casey A, Courcelle J (2006) Nascent DNA processing by RecJ favors lesion repair over translesion synthesis at arrested replication forks in Escherichia coli. Proc Natl Acad Sci USA 103:9154–9159
Crabbe L, Verdun RE, Haggblom CI, Karlseder J (2004) Defective telomere lagging strand synthesis in cells lacking WRN helicase activity. Science 306:1951–1953
Cui S, Arosio D, Doherty KM, Brosh RM, Falaschi A, Vindigni A (2004) Analysis of the unwinding activity of the dimeric RECQ1 helicase in the presence of human replication protein A. Nucleic Acids Res 32:2158–2170
Davalos AR, Campisi J (2003) Bloom syndrome cells undergo p53-dependent apoptosis and delayed assembly of BRCA1 and NBS1 repair complexes at stalled replication forks. J Cell Biol 162:1197–1209
Davalos AR, Kaminker P, Hansen RK, Campisi J (2004) ATR and ATM-Dependent Movement of BLM Helicase during Replication Stress Ensures Optimal ATM Activation and 53BP1 Focus Formation. Cell Cycle 3:1579–1586
Davies SL, North PS, Dart A, Lakin ND, Hickson ID (2004) Phosphorylation of the Bloom’s syndrome helicase and its role in recovery from S-phase arrest. Mol Cell Biol 24:1279–1291
Davies SL, North PS, Hickson ID (2007) Role for BLM in replication-fork restart and suppression of origin firing after replicative stress. Nat Struct Mol Biol 14:677–679
Doherty KM, Sommers JA, Gray MD, Lee JW, von Kobbe C, Thoma NH, Kureekattil RP, Kenny MK, Brosh RM (2005) Physical and functional mapping of the replication protein a interaction domain of the werner and bloom syndrome helicases. J Biol Chem 280:29494–29505
Dutertre S, Ababou M, Onclercq R, Delic J, Chatton B, Jaulin C, Amor-Gueret M (2000) Cell cycle regulation of the endogenous wild type Bloom’s syndrome DNA helicase. Oncogene 19:2731–2738
Ellis NA, Groden J, Ye TZ, Straughen J, Lennon DJ, Ciocci S, Proytcheva M, German J (1995) The Bloom’s syndrome gene product is homologous to RecQ helicases. Cell 83:655–666
Frei C, Gasser SM (2000) The yeast Sgs1p helicase acts upstream of Rad53p in the DNA replication checkpoint and colocalizes with Rad53p in S-phase-specific foci. Genes Dev 14:81–96
Fujiwara Y, Higashikawa T, Tatsumi M (1977) A retarded rate of DNA replication and normal level of DNA repair in Werner’s syndrome fibroblasts in culture. J Cell Physiol 92:365–374
Fujiwara Y, Kano Y, Ichihashi M, Nakao Y, Matsumara T (1985) Abnormal fibroblast aging and DNA replication in the Werner syndrome. Adv Exp Med Biol 190:459–477
Garcia PL, Bradley G, Hayes CJ, Krintel S, Soultanas P, Janscak P (2004) RPA alleviates the inhibitory effect of vinylphosphonate internucleotide linkages on DNA unwinding by BLM and WRN helicases. Nucleic Acids Res 32:3771–3778
Giannelli F, Benson PF, Pawsey SA, Polani PE (1977) Ultraviolet light sensitivity and delayed DNA-chain maturation in Bloom’s syndrome fibroblasts. Nature 265:466–469
Han ES, Cooper DL, Persky NS, Sutera VA, Whitaker RD, Montello ML, Lovett ST (2006) RecJ exonuclease: substrates, products and interaction with SSB. Nucleic Acids Res 34:1084–1091
Hanaoka F, Takeuchi F, Matsumura T, Goto M, Miyamoto T, Yamada M (1983) Decrease in the average size of replicons in a Werner syndrome cell line by Simian virus 40 infection. Exp Cell Res 144:463–467
Hanaoka F, Yamada M, Takeuchi F, Goto M, Miyamoto T, Hori T (1985) Autoradiographic studies of DNA replication in Werner’s syndrome cells. Adv Exp Med Biol 190:439–457
Hand R, German J (1975) A retarded rate of DNA chain growth in Bloom’s syndrome. Proc Natl Acad Sci USA 72:758–762
Hartung F, Puchta H (2006) The RecQ gene family in plants. J Plant Physiol 163:287–296
Heller RC, Marians KJ (2006) Replisome assembly and the direct restart of stalled replication forks. Nat Rev Mol Cell Biol 7:932–943
Huber MD, Duquette ML, Shiels JC, Maizels N (2006) A conserved G4 DNA binding domain in RecQ family helicases. J Mol Biol 358:1071–1080
Imamura O, Campbell JL (2003) The human Bloom syndrome gene suppresses the DNA replication and repair defects of yeast dna2 mutants. Proc Natl Acad Sci USA 100:8193–8198
Kamath-Loeb AS, Johansson E, Burgers PMJ, Loeb LA (2000) Functional interaction between the Werner syndrome protein and DNA polymerase δ. Proc Natl Acad Sci USA 97:4603–4608
Kamath-Loeb AS, Loeb LA, Johansson E, Burgers PMJ, Fry M (2001) Interactions between the Werner syndrome helicase and DNA polymerase δ specifically facilitate copying of tetraplex and hairpin structures of the D(CGG)n trinucleotide repeat sequence. J Biol Chem 276:16439–16446
Kanagaraj R, Saydam N, Garcia PL, Zheng L, Janscak P (2006) Human RECQ5β helicase promotes strand exchange on synthetic DNA structures resembling a stalled replication fork. Nucleic Acids Res 34:5217–5231
Kang S, Ohshima K, Shimizu M, Amirhaeri S, Wells RD (1995) Pausing of DNA synthesis in vitro at specific loci in CTG and CGG triplet repeats from human hereditary disease genes. J Biol Chem 270:27014–27021
Kitao S, Shimamoto A, Goto M, Miller RW, Smithson WA, Lindor NM, Furuichi Y (1999) Mutations in RECQL4 cause a subset of cases of Rothmund-Thomson syndrome. Nat Genet 22:82–84
Lebel M, Spillare EA, Harris CC, Leder P (1999) The Werner syndrome gene product co-purifies with the DNA replication complex and interacts with PCNA and topoisomerase I. J Biol Chem 274:37795–37799
Lecointe F, Serena C, Velten M, Costes A, McGovern S, Meile JC, Errington J, Ehrlich SD, Noirot P, Polard P (2007) Anticipating chromosomal replication fork arrest: SSB targets repair DNA helicases to active forks. EMBO J 26:4239–4251
Li W, Kim SM, Lee J, Dunphy WG (2004) Absence of BLM leads to accumulation of chromosomal DNA breaks during both unperturbed and disrupted S phases. J Cell Biol 165:801–812
Liao S, Graham J, Yan H (2000) The function of Xenopus Bloom’s syndrome protein homolog (xBLM) in DNA replication. Genes Dev 14:2570–2575
Liberi G, Maffioletti G, Lucca C, Chiolo I, Baryshnikova A, Cotta-Ramusino C, Lopes M, Pellicioli A, Haber JE, Foiani M (2005) Rad51-dependent DNA structures accumulate at damaged replication forks in sgs1 mutants defective in the yeast ortholog of BLM RecQ helicase. Genes Dev 19:339–350
Lohka MJ, Masui Y (1983) Formation in vitro of sperm pronuclei and mitotic chromosomes induced by amphibian ooplasmic components. Science 220:719–721
Lönn U, Lönn S, Nylen U, Winblad G, German J (1990) An abnormal profile of DNA replication intermediates in Bloom’s syndrome. Cancer Res 50:3141–3145
Lucca C, Vanoli F, Cotta-Ramusino C, Pellicioli A, Liberi G, Haber J, Foiani M (2004) Checkpoint-mediated control of replisome-fork association and signalling in response to replication pausing. Oncogene 23:1206–1213
Machwe A, Lozada EM, Xiao L, Orren DK (2006a) Competition between the DNA unwinding and strand pairing activities of the Werner and Bloom syndrome proteins. BMC Mol Biol 7:1
Machwe A, Xiao L, Groden J, Orren DK (2006b) The Werner and Bloom syndrome proteins catalyze regression of a model replication fork. Biochemistry (Mosc) 45:13939–13946
Macris MA, Krejci L, Bussen W, Shimamoto A, Sung P (2006) Biochemical characterization of the RECQ4 protein, mutated in Rothmund-Thomson syndrome. DNA Repair (Amst) 5:172–180
Marchetti MA, Kumar S, Hartsuiker E, Maftahi M, Carr AM, Freyer GA, Burhans WC, Huberman JA (2002) A single unbranched S-phase DNA damage and replication fork blockage checkpoint pathway. Proc Natl Acad Sci USA 99:7472–7477
Matsuno K, Kumano M, Kubota Y, Hashimoto Y, Takisawa H (2006) The N-terminal noncatalytic region of Xenopus RecQ4 is required for chromatin binding of DNA polymerase alpha in the initiation of DNA replication. Mol Cell Biol 26:4843–4852
McGlynn P, Lloyd RG (2001) Rescue of stalled replication forks by RecG: simultaneous translocation on the leading and lagging strand templates supports an active DNA unwinding model of fork reversal and Holliday junction formation. Proc Natl Acad Sci USA 98:8227–8234
McGlynn P, Lloyd RG, Marians KJ (2001) Formation of Holliday junctions by regression of nascent DNA in intermediates containing stalled replication forks: RecG stimulates regression even when the DNA is negatively supercoiled. Proc Natl Acad Sci USA 98:8235–8240
Melo J, Toczyski D (2002) A unified view of the DNA-damage checkpoint. Curr Opin Cell Biol 14:237–245
Morimatsu K, Kowalczykowski SC (2003) RecFOR proteins load RecA protein onto gapped DNA to accelerate DNA strand exchange: a universal step of recombinational repair. Mol Cell 11:1337–1347
Newport J (1987) Nuclear reconstitution in vitro: stages of assembly around protein-free DNA. Cell 48:205–217
Park SJ, Lee YJ, Beck BD, Lee SH (2006) A Positive Involvement of RecQL4 in UV-Induced S-Phase Arrest. DNA Cell Biol 25:696–703
Pichierri P, Franchitto A, Mosesso P, Palitti F (2001) Werner’s syndrome protein is required for correct recovery after replication arrest and DNA damage induced in S-phase of cell cycle. Mol Biol Cell 12:2412–2421
Pichierri P, Rosselli F, Franchitto A (2003) Werner’s syndrome protein is phosphorylated in an ATR/ATM-dependent manner following replication arrest and DNA damage induced during the S phase of the cell cycle. Oncogene 22:1491–1500
Poot M, Hoehn H, Runger TM, Martin GM (1992) Impaired S-phase transit of Werner syndrome expressed in lymphoblastoid cells. Exp Cell Res 202:267–273
Ralf C, Hickson ID, Wu L (2006) The Bloom’s syndrome helicase can promote the regression of a model replication fork. J Biol Chem 281:22839–22846
Rassool FV, North PS, Mufti GJ, Hickson ID (2003) Constitutive DNA damage is linked to DNA replication abnormalities in Bloom’s syndrome cells. Oncogene 22:8749–8757
Rodriguez-Lopez AM, Jackson DA, Iborra F, Cox LS (2002) Asymmetry of DNA replication fork progression in Werner’s syndrome. Aging Cell 1:30–39
Rodriguez-Lopez AM, Jackson DA, Nehlin JO, Iborra F, Warren AV, Cox LS (2003) Characterisation of the interaction between WRN, the helicase/exonuclease defective in progeroid Werner’s syndrome, and an essential replication factor, PCNA. Mech Ageing Dev 124:167–174
Sakamoto S, Nishikawa K, Heo SJ, Goto M, Furuichi Y, Shimamoto A (2001) Werner helicase relocates into nuclear foci in response to DNA damaging agents and co-localizes with RPA and Rad51. Genes Cells 6:421–430
Sangrithi MN, Bernal JA, Madine M, Philpott A, Lee J, Dunphy WG, Venkitaraman AR (2005) Initiation of DNA replication requires the RECQL4 protein mutated in Rothmund-Thomson syndrome. Cell 121:887–898
Sasakawa N, Fukui T, Waga S (2006) Accumulation of FFA-1, the Xenopus homolog of Werner helicase, and DNA polymerase delta on chromatin in response to replication fork arrest. J Biochem (Tokyo) 140:95–103
Sharma S, Otterlei M, Sommers JA, Driscoll HC, Dianov GL, Kao HI, Bambara RA, Brosh RM (2004a) WRN helicase and FEN-1 form a complex upon replication arrest and together process branchmigrating DNA structures associated with the replication fork. Mol Biol Cell 15:734–750
Sharma S, Sommers JA, Brosh RM (2004b) In vivo function of the conserved non-catalytic domain of Werner syndrome helicase in DNA replication. Hum Mol Genet 13:2247–2261
Sharma S, Sommers JA, Wu L, Bohr VA, Hickson ID, Brosh RM (2004c) Stimulation of Flap Endonuclease-1 by the Bloom’s Syndrome Protein. J Biol Chem 279:9847–9856
Sharma S, Doherty KM, Brosh RM (2006) Mechanisms of RecQ helicases in pathways of DNA metabolism and maintenance of genomic stability. Biochem J 398:319–337
Shiratori M, Suzuki T, Itoh C, Goto M, Furuichi Y, Matsumoto T (2002) WRN helicase accelerates the transcription of ribosomal RNA as a component of an RNA polymerase I-associated complex. Oncogene 21:2447–2454
Siitonen HA, Kopra O, Kaariainen H, Haravuori H, Winter RM, Saamanen AM, Peltonen L, Kestila M (2003) Molecular defect of RAPADILINO syndrome expands the phenotype spectrum of RECQL diseases. Hum Mol Genet 12:2837–2844
Stewart E, Chapman CR, Al-Khodairy F, Carr AM, Enoch T (1997) rqh1+, a fission yeast gene related to the Bloom’s and Werner’s syndrome genes, is required for reversible S phase arrest. EMBO J 16:2682–2692
Szekely AM, Chen YH, Zhang C, Oshima J, Weissman SM (2000) Werner protein recruits DNA polymerase δ to the nucleolus. Proc Natl Acad Sci USA 97:11365–11370
Takeuchi F, Hanaoka F, Goto M, Akaoka I, Hori T, Yamada M, Miyamoto T (1982a) Altered frequency of initiation sites of DNA replication in Werner’s syndrome cells. Hum Genet 60:365–368
Takeuchi F, Hanaoka F, Goto M, Yamada M, Miyamoto T (1982b) Prolongation of S phase and whole cell cycle in Werner’s syndrome fibroblasts. Exp Gerontol 17:473–480
Tourriere H, Pasero P (2007) Maintenance of fork integrity at damaged DNA and natural pause sites. DNA Repair (Amst) 6:900–913
Usdin K, Woodford KJ (1995) CGG repeats associated with DNA instability and chromosome fragility form structures that block DNA synthesis in vitro. Nucleic Acids Res 23:4202–4209
Van Maldergem L, Siitonen HA, Jalkh N, Chouery E, De Roy M, Delague V, Muenke M, Jabs EW, Cai J, Wang LL, Plon SE, Fourneau C, Kestila M, Gillerot Y, Megarbane A, Verloes A (2006) Revisiting the craniosynostosis-radial ray hypoplasia association: Baller-Gerold syndrome caused by mutations in the RECQL4 gene. J Med Genet 43:148–152
Versini G, Comet I, Wu M, Hoopes L, Schwob E, Pasero P (2003) The yeast Sgs1 helicase is differentially required for genomic and ribosomal DNA replication. EMBO J 22:1939–1949
Wang W, Bambara RA (2005) Human Bloom protein stimulates flap endonuclease 1 activity by resolving DNA secondary structure. J Biol Chem 280:5391–5399
Wu L (2007) Role of the BLM helicase in replication fork management. DNA Repair (Amst) 6:936–944
Wu L, Hickson ID (2006) DNA helicases required for homologous recombination and repair of damaged replication forks. Annu Rev Genet 40:279–306
Yan H, Newport J (1995) FFA-1, a protein that promotes the formation of replication centers within nuclei. Science 269:1883–1885
Yan H, Chen CY, Kobayashi R, Newport J (1998) Replication focus-forming activity 1 and the Werner syndrome gene product. Nat Genet 19:375–378
Yang W (2000) Structure and function of mismatch repair proteins. Mutat Res 460:245–56
Yankiwski V, Marciniak RA, Guarente L, Neff NF (2000) Nuclear structure in normal and Bloom syndrome cells. Proc Natl Acad Sci USA 97:5214–5219
Ye L, Nakura J, Morishima A, Miki T (1998) Transcriptional activation by the Werner syndrome gene product in yeast. Exp Gerontol 33:805–812
Yu CE, Oshima J, Fu YH, Wijsman EM, Hisama F, Alisch R, Matthews S, Nakura J, Miki T, Ouais S, Martin GM, Mulligan J, Schellenberg GD (1996) Positional cloning of the Werner’s syndrome gene. Science 272:258–262
Acknowledgement
The authors wish to thank members of the Genome Integrity Group for useful discussions, Drs. K. Hanada, P. McHugh and L. Wu for critical reading of the manuscript, and Miss E. Weston for preparation of the manuscript. This work was supported by the Cancer Research UK.
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Bachrati, C.Z., Hickson, I.D. RecQ helicases: guardian angels of the DNA replication fork. Chromosoma 117, 219–233 (2008). https://doi.org/10.1007/s00412-007-0142-4
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DOI: https://doi.org/10.1007/s00412-007-0142-4