DNA replication and cancer: From dysfunctional replication origin activities to therapeutic opportunities.

A dividing cell has to duplicate its DNA precisely once during the cell cycle to preserve genome integrity avoiding the accumulation of genetic aberrations that promote diseases such as cancer. A large number of endogenous impacts can challenge DNA replication and cells harbor a battery of pathways to promote genome integrity during DNA replication. This includes suppressing new replication origin firing, stabilization of replicating forks, and the safe restart of forks to prevent any loss of genetic information. Here, we describe mechanisms by which oncogenes can interfere with DNA replication thereby causing DNA replication stress and genome instability. Further, we describe cellular and systemic responses to these insults with a focus on DNA replication restart pathways. Finally, we discuss the therapeutic potential of exploiting intrinsic replicative stress in cancer cells for targeted therapy.

[1]  L. Haracska,et al.  Role of Double-Stranded DNA Translocase Activity of Human HLTF in Replication of Damaged DNA , 2009, Molecular and Cellular Biology.

[2]  P. Jeggo,et al.  The role of the DNA damage response pathways in brain development and microcephaly: insight from human disorders. , 2008, DNA repair.

[3]  Anindya Dutta,et al.  A p53-dependent checkpoint pathway prevents rereplication. , 2003, Molecular cell.

[4]  Yan Huang,et al.  Penetrance of biallelic SMARCAL1 mutations is associated with environmental and genetic disturbances of gene expression. , 2012, Human molecular genetics.

[5]  J. Cook,et al.  Replication licensing promotes cyclin D1 expression and G1 progression in untransformed human cells , 2009, Cell cycle.

[6]  I. Hickson,et al.  FBH1 co-operates with MUS81 in inducing DNA double-strand breaks and cell death following replication stress , 2013, Nature Communications.

[7]  Anne-Sophie Boyer,et al.  The human specialized DNA polymerases and non-B DNA: vital relationships to preserve genome integrity. , 2013, Journal of molecular biology.

[8]  Penny A Jeggo,et al.  Mutations in ORC1, encoding the largest subunit of the origin recognition complex, cause microcephalic primordial dwarfism resembling Meier-Gorlin syndrome , 2011, Nature Genetics.

[9]  Down-regulation of DNA polymerases kappa, eta, iota, and zeta in human lung, stomach, and colorectal cancers. , 2005, Cancer letters.

[10]  S. Boulton,et al.  RTEL1 Dismantles T Loops and Counteracts Telomeric G4-DNA to Maintain Telomere Integrity , 2012, Cell.

[11]  Z. Tu,et al.  Inhibiting the expression of DNA replication-initiation proteins induces apoptosis in human cancer cells. , 2003, Cancer research.

[12]  L. Blanco,et al.  Repriming of DNA synthesis at stalled replication forks by human PrimPol , 2013, Nature Structural &Molecular Biology.

[13]  J. Bartek,et al.  DNA damage signalling guards against activated oncogenes and tumour progression , 2007, Oncogene.

[14]  A. Aguilera,et al.  Replication stress and cancer , 2015, Nature Reviews Cancer.

[15]  J. Blow,et al.  Chk1 inhibits replication factory activation but allows dormant origin firing in existing factories , 2010, The Journal of cell biology.

[16]  B. Clurman,et al.  Cyclin E in normal and neoplastic cell cycles , 2005, Oncogene.

[17]  Thanos D Halazonetis,et al.  DNA replication stress as a hallmark of cancer. , 2015, Annual review of pathology.

[18]  Aniruddh Kashyap,et al.  Germline RECQL mutations are associated with breast cancer susceptibility , 2015, Nature Genetics.

[19]  S. Cantor,et al.  Hereditary breast cancer and the BRCA1-associated FANCJ/BACH1/BRIP1. , 2011, Future oncology.

[20]  Jiri Bartek,et al.  Replication stress links structural and numerical cancer chromosomal instability , 2013, Nature.

[21]  D. Patel,et al.  ORC1 BAH domain links H4K20me2 to DNA replication licensing and Meier-Gorlin syndrome , 2012, Nature.

[22]  Bruce Stillman,et al.  Deregulation of cyclin E in human cells interferes with prereplication complex assembly , 2004, The Journal of cell biology.

[23]  J. Bartek,et al.  Loss of Geminin induces rereplication in the presence of functional p53 , 2004, The Journal of cell biology.

[24]  N. Rhind,et al.  DNA replication timing. , 2013, Cold Spring Harbor perspectives in biology.

[25]  Chikahide Masutani,et al.  The XPV (xeroderma pigmentosum variant) gene encodes human DNA polymerase η , 1999, Nature.

[26]  Cindy Follonier,et al.  Friedreich's ataxia–associated GAA repeats induce replication-fork reversal and unusual molecular junctions , 2013, Nature Structural &Molecular Biology.

[27]  J. Julian Blow,et al.  Replication licensing and cancer — a fatal entanglement? , 2008, Nature Reviews Cancer.

[28]  A. Egashira,et al.  Double-Strand Break Repair-Independent Role for BRCA2 in Blocking Stalled Replication Fork Degradation by MRE11 , 2011, Cell.

[29]  Jiri Bartek,et al.  Human Fbh1 helicase contributes to genome maintenance via pro- and anti-recombinase activities , 2009, The Journal of cell biology.

[30]  J. Bartek,et al.  Inhibition of Human Chk1 Causes Increased Initiation of DNA Replication, Phosphorylation of ATR Targets, and DNA Breakage , 2005, Molecular and Cellular Biology.

[31]  J. Peters,et al.  Cell cycle- and cell growth-regulated proteolysis of mammalian CDC6 is dependent on APC-CDH1. , 2000, Genes & development.

[32]  Thomas Helleday,et al.  Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase , 2005, Nature.

[33]  L. Loeb,et al.  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* , 2001, The Journal of Biological Chemistry.

[34]  V. Bohr,et al.  RecQ helicases in DNA double strand break repair and telomere maintenance. , 2012, Mutation research.

[35]  S. Elledge,et al.  Polyubiquitinated PCNA recruits the ZRANB3 translocase to maintain genomic integrity after replication stress. , 2012, Molecular cell.

[36]  B. Lopez,et al.  Replication Stress in Mammalian Cells and Its Consequences for Mitosis , 2015, Genes.

[37]  N. Mailand,et al.  ATR Prohibits Replication Catastrophe by Preventing Global Exhaustion of RPA , 2013, Cell.

[38]  F. Mulero,et al.  A mouse model of ATR-Seckel shows embryonic replicative stress and accelerated aging , 2009, Nature Genetics.

[39]  Ricky D. Edmondson,et al.  GINS maintains association of Cdc45 with MCM in replisome progression complexes at eukaryotic DNA replication forks , 2006, Nature Cell Biology.

[40]  Anindya Dutta,et al.  NEDD8-targeting drug MLN4924 elicits DNA rereplication by stabilizing Cdt1 in S phase, triggering checkpoint activation, apoptosis, and senescence in cancer cells. , 2010, Cancer research.

[41]  S. Mirkin.  Expandable DNA repeats and human disease , 2007, Nature.

[42]  Jeanette Gowen Cook,et al.  Origin licensing and p53 status regulate Cdk2 activity during G1 , 2009, Cell cycle.

[43]  J. Toth,et al.  A gatekeeper residue for NEDD8-activating enzyme inhibition by MLN4924. , 2012, Cell reports.

[44]  D. Averbeck,et al.  Characterisation of homologous recombination induced by replication inhibition in mammalian cells , 2020 .

[45]  M. Lopes,et al.  Rad51 protects nascent DNA from Mre11 dependent degradation and promotes continuous DNA synthesis , 2010, Nature Structural &Molecular Biology.

[46]  Raquel Herrador,et al.  Rad51-mediated replication fork reversal is a global response to genotoxic treatments in human cells , 2015, The Journal of cell biology.

[47]  J. Diffley,et al.  DNA Replication and Oncogene-Induced Replicative Stress , 2014, Current Biology.

[48]  Y. Pommier,et al.  Mus81-mediated DNA cleavage resolves replication forks stalled by topoisomerase I–DNA complexes , 2011, The Journal of cell biology.

[49]  Y. Pommier.  Drugging topoisomerases: lessons and challenges. , 2013, ACS chemical biology.

[50]  I. Lahiri,et al.  Human polymerase kappa uses a template-slippage deletion mechanism, but can realign the slipped strands to favour base substitution mutations over deletions , 2013, Nucleic acids research.

[51]  S. Jentsch,et al.  The RAD6 DNA Damage Tolerance Pathway Operates Uncoupled from the Replication Fork and Is Functional Beyond S Phase , 2010, Cell.

[52]  Akiko Shimamura,et al.  Fanconi anemia pathway-deficient tumor cells are hypersensitive to inhibition of ataxia telangiectasia mutated. , 2007, The Journal of clinical investigation.

[53]  D. Jackson,et al.  How dormant origins promote complete genome replication. , 2011, Trends in biochemical sciences.

[54]  E. Lecona,et al.  Replication stress and cancer: it takes two to tango. , 2014, Experimental cell research.

[55]  Olivier Hyrien,et al.  Paradoxes of eukaryotic DNA replication: MCM proteins and the random completion problem , 2003, BioEssays : news and reviews in molecular, cellular and developmental biology.

[56]  L. Zou,et al.  DNA damage sensing by the ATM and ATR kinases. , 2013, Cold Spring Harbor perspectives in biology.

[57]  R. Heller,et al.  Replication fork reactivation downstream of a blocked nascent leading strand , 2006, Nature.

[58]  Attila Tóth,et al.  APCCdc20 promotes exit from mitosis by destroying the anaphase inhibitor Pds1 and cyclin Clb5 , 1999, Nature.

[59]  K. Cimprich,et al.  Causes and consequences of replication stress , 2013, Nature Cell Biology.

[60]  Tomoaki Tanaka,et al.  Negative regulation of NEDD8 conjugation pathway by novel molecules and agents for anticancer therapy. , 2013, Current pharmaceutical design.

[61]  B. Dutrillaux,et al.  Common fragile sites: mechanisms of instability revisited. , 2012, Trends in genetics : TIG.

[62]  Julie Bianchi,et al.  PrimPol Bypasses UV Photoproducts during Eukaryotic Chromosomal DNA Replication , 2013, Molecular cell.

[63]  M. Lopes,et al.  Fork Reversal and ssDNA Accumulation at Stalled Replication Forks Owing to Checkpoint Defects , 2002, Science.

[64]  T. Pandita,et al.  Cdt1 transgenic mice develop lymphoblastic lymphoma in the absence of p53 , 2005, Oncogene.

[65]  J. Walter,et al.  Replication-dependent destruction of Cdt1 limits DNA replication to a single round per cell cycle in Xenopus egg extracts. , 2005, Genes & development.

[66]  Jingchuan Sun,et al.  A double-hexameric MCM2-7 complex is loaded onto origin DNA during licensing of eukaryotic DNA replication , 2009, Proceedings of the National Academy of Sciences.

[67]  M. Botchan,et al.  Isolation of the Cdc45/Mcm2–7/GINS (CMG) complex, a candidate for the eukaryotic DNA replication fork helicase , 2006, Proceedings of the National Academy of Sciences.

[68]  J. Bartek,et al.  Functional interplay between the DNA-damage-response kinase ATM and ARF tumour suppressor protein in human cancer , 2013, Nature Cell Biology.

[69]  N. Maizels,et al.  The Bloom’s Syndrome Helicase Unwinds G4 DNA* , 1998, The Journal of Biological Chemistry.

[70]  J. Qin,et al.  ATR phosphorylates SMARCAL1 to prevent replication fork collapse. , 2013, Genes & development.

[71]  Penny A. Johnson,et al.  XRCC3 and Rad51 modulate replication fork progression on damaged vertebrate chromosomes. , 2003, Molecular cell.

[72]  Y. Tatsumi,et al.  Deregulation of Cdt1 induces chromosomal damage without rereplication and leads to chromosomal instability , 2006, Journal of Cell Science.

[73]  T. Halazonetis,et al.  Genomic instability — an evolving hallmark of cancer , 2010, Nature Reviews Molecular Cell Biology.

[74]  Hong Wu,et al.  A distinct replication fork protection pathway connects Fanconi anemia tumor suppressors to RAD51-BRCA1/2. , 2012, Cancer cell.

[75]  P. Jallepalli,et al.  ATR-mediated phosphorylation of FANCI regulates dormant origin firing in response to replication stress. , 2015, Molecular cell.

[76]  Xun Hu,et al.  Down-regulation of DNA polymerases κ, η, ι, and ζ in human lung, stomach, and colorectal cancers , 2005 .

[77]  D. Wigley,et al.  Pumps, paradoxes and ploughshares: mechanism of the MCM2-7 DNA helicase. , 2005, Trends in biochemical sciences.

[78]  S. Elledge,et al.  Minichromosome maintenance proteins are direct targets of the ATM and ATR checkpoint kinases. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[79]  P. McGlynn,et al.  Replication fork reversal and the maintenance of genome stability , 2009, Nucleic acids research.

[80]  Replication stress links structural and numerical cancer chromosomal instability (vol 494, pg 492, 2013) , 2013 .

[81]  S. Boulton,et al.  RTEL1: functions of a disease-associated helicase. , 2014, Trends in cell biology.

[82]  B. Strauss,et al.  A model for replication repair in mammalian cells. , 1976, Journal of molecular biology.

[83]  P. Ménard,et al.  Nascent chromatin capture proteomics determines chromatin dynamics during DNA replication and identifies unknown fork components , 2014, Nature Cell Biology.

[84]  Peter G. Smith,et al.  The NEDD8 Conjugation Pathway and Its Relevance in Cancer Biology and Therapy. , 2010, Genes & cancer.

[85]  R. Syljuåsen,et al.  Safeguarding genome integrity: the checkpoint kinases ATR, CHK1 and WEE1 restrain CDK activity during normal DNA replication , 2011, Nucleic acids research.

[86]  C. McMurray.  Mechanisms of trinucleotide repeat instability during human development , 2010, Nature Reviews Genetics.

[87]  T. Helleday,et al.  Chk1 promotes replication fork progression by controlling replication initiation , 2010, Proceedings of the National Academy of Sciences.

[88]  J. Al-Aama,et al.  Meier–Gorlin syndrome genotype–phenotype studies: 35 individuals with pre-replication complex gene mutations and 10 without molecular diagnosis , 2012, European Journal of Human Genetics.

[89]  P. Jeggo,et al.  Identification of the First ATRIP–Deficient Patient and Novel Mutations in ATR Define a Clinical Spectrum for ATR–ATRIP Seckel Syndrome , 2012, PLoS genetics.

[90]  Robert E. Johnson,et al.  Efficient bypass of a thymine-thymine dimer by yeast DNA polymerase, Poleta. , 1999, Science.

[91]  Junjie Chen,et al.  The HARP-like domain-containing protein AH2/ZRANB3 binds to PCNA and participates in cellular response to replication stress. , 2012, Molecular cell.

[92]  Aristides G. Eliopoulos,et al.  Cdc6 expression represses E-cadherin transcription and activates adjacent replication origins , 2011, The Journal of cell biology.

[93]  C. Cazaux,et al.  Aberrant expression of alternative DNA polymerases: a source of mutator phenotype as well as replicative stress in cancer. , 2010, Seminars in cancer biology.

[94]  Aaron Bensimon,et al.  Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication , 2006, Nature.

[95]  K. Shin‐ya,et al.  FANCJ Helicase Defective in Fanconia Anemia and Breast Cancer Unwinds G-Quadruplex DNA To Defend Genomic Stability , 2008, Molecular and Cellular Biology.

[96]  J. Sale,et al.  Epigenetic Instability due to Defective Replication of Structured DNA , 2010, Molecular cell.

[97]  Peter Bouwman,et al.  The effects of deregulated DNA damage signalling on cancer chemotherapy response and resistance , 2012, Nature Reviews Cancer.

[98]  Thomas Helleday,et al.  Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase , 2007, Nature.

[99]  Jiri Bartek,et al.  Phosphorylation of mammalian CDC6 by Cyclin A/CDK2 regulates its subcellular localization , 1999, The EMBO journal.

[100]  J. Groden,et al.  The Werner and Bloom syndrome proteins catalyze regression of a model replication fork. , 2006, Biochemistry.

[101]  J. Hamlin,et al.  Cdc45 Limits Replicon Usage from a Low Density of preRCs in Mammalian Cells , 2011, PloS one.

[102]  T. Taguchi,et al.  Aphidicolin prevents mitotic cell division by interfering with the activity of DNA polymerase-α , 1978, Nature.

[103]  A. Constantinou,et al.  Remodeling of DNA replication structures by the branch point translocase FANCM , 2008, Proceedings of the National Academy of Sciences.

[104]  J. Diffley,et al.  Concerted Loading of Mcm2–7 Double Hexamers around DNA during DNA Replication Origin Licensing , 2009, Cell.

[105]  S. Patzke,et al.  Cyclin-Dependent Kinase Suppression by WEE1 Kinase Protects the Genome through Control of Replication Initiation and Nucleotide Consumption , 2012, Molecular and Cellular Biology.

[106]  J. Maciejewski,et al.  The NEDD8-Activating Enzyme Inhibitor MLN4924 Disrupts Nucleotide Metabolism and Augments the Efficacy of Cytarabine , 2014, Clinical Cancer Research.

[107]  Raquel Herrador,et al.  Topoisomerase I poisoning results in PARP-mediated replication fork reversal , 2012, Nature Structural &Molecular Biology.

[108]  Jonathan R. Hall,et al.  Cdc6 stability is regulated by the Huwe1 ubiquitin ligase after DNA damage. , 2007, Molecular biology of the cell.

[109]  M. DePamphilis,et al.  Ubiquitylation, phosphorylation and Orc2 modulate the subcellular location of Orc1 and prevent it from inducing apoptosis , 2006, Journal of Cell Science.

[110]  J. Diffley,et al.  CDKs Promote DNA Replication Origin Licensing in Human Cells by Protecting Cdc6 from APC/C-Dependent Proteolysis , 2005, Cell.

[111]  M. Lopes,et al.  Human RECQ1 promotes restart of replication forks reversed by DNA topoisomerase I inhibition , 2013, Nature Structural &Molecular Biology.

[112]  C. M. Sanders.  Human Pif1 helicase is a G-quadruplex DNA-binding protein with G-quadruplex DNA-unwinding activity. , 2010, The Biochemical journal.

[113]  J. Blow,et al.  MCM2-7 Form Double Hexamers at Licensed Origins in Xenopus Egg Extract* , 2011, The Journal of Biological Chemistry.

[114]  A. Jackson,et al.  Mechanisms and pathways of growth failure in primordial dwarfism. , 2011, Genes & development.

[115]  Oscar Fernandez-Capetillo,et al.  Targeting ATR and Chk1 kinases for cancer treatment: A new model for new (and old) drugs , 2011, Molecular oncology.

[116]  A. Thompson,et al.  DNA polymerase θ up-regulation is associated with poor survival in breast cancer, perturbs DNA replication, and promotes genetic instability , 2010, Proceedings of the National Academy of Sciences.

[117]  Xin Quan Ge,et al.  Dormant origins licensed by excess Mcm2-7 are required for human cells to survive replicative stress. , 2007, Genes & development.

[118]  Jiri Bartek,et al.  Targeting the checkpoint kinases: chemosensitization versus chemoprotection , 2004, Nature Reviews Cancer.

[119]  Liang Zhao,et al.  FDA Approval Summary: Olaparib Monotherapy in Patients with Deleterious Germline BRCA-Mutated Advanced Ovarian Cancer Treated with Three or More Lines of Chemotherapy , 2015, Clinical Cancer Research.

[120]  S. Balasubramanian,et al.  FANCJ coordinates two pathways that maintain epigenetic stability at G-quadruplex DNA , 2011, Nucleic acids research.

[121]  P. Klatt,et al.  Oncogenic activity of Cdc6 through repression of the INK4/ARF locus , 2006, Nature.

[122]  R. Brosh.  DNA helicases involved in DNA repair and their roles in cancer , 2013, Nature Reviews Cancer.

[123]  M. Dobbelstein,et al.  Exploiting replicative stress to treat cancer , 2015, Nature Reviews Drug Discovery.

[124]  M. Yaffe,et al.  The combined status of ATM and p53 link tumor development with therapeutic response. , 2009, Genes & development.

[125]  Dimitris Kletsas,et al.  Deregulated overexpression of hCdt1 and hCdc6 promotes malignant behavior. , 2007, Cancer research.

[126]  Jamie K Teer,et al.  Acute Reduction of an Origin Recognition Complex (ORC) Subunit in Human Cells Reveals a Requirement of ORC for Cdk2 Activation* , 2005, Journal of Biological Chemistry.

[127]  E. Schwob,et al.  Excess MCM proteins protect human cells from replicative stress by licensing backup origins of replication , 2008, Proceedings of the National Academy of Sciences.

[128]  M. Botchan,et al.  Activation of the MCM2-7 helicase by association with Cdc45 and GINS proteins. , 2010, Molecular cell.

[129]  E. Salido,et al.  PrimPol, an Archaic Primase/Polymerase Operating in Human Cells , 2013, Molecular cell.

[130]  E. Friedberg.  Suffering in silence: the tolerance of DNA damage , 2005, Nature Reviews Molecular Cell Biology.

[131]  Irene Saugar,et al.  Tolerating DNA damage during eukaryotic chromosome replication. , 2014, Experimental cell research.

[132]  T. Helleday,et al.  Different Roles for Nonhomologous End Joining and Homologous Recombination following Replication Arrest in Mammalian Cells , 2002, Molecular and Cellular Biology.

[133]  W. Gu,et al.  Non-transcriptional control of DNA replication by c-Myc , 2007, Nature.

[134]  S. Boulton,et al.  Metabolism of DNA secondary structures at the eukaryotic replication fork. , 2014, DNA repair.

[135]  Zhan Xiao,et al.  Selective Chk1 inhibitors differentially sensitize p53‐deficient cancer cells to cancer therapeutics , 2006, International journal of cancer.

[136]  Thomas Helleday,et al.  Overexpression of POLQ Confers a Poor Prognosis in Early Breast Cancer Patients , 2010, Oncotarget.

[137]  M. Botchan,et al.  Stalled fork rescue via dormant replication origins in unchallenged S phase promotes proper chromosome segregation and tumor suppression. , 2011, Molecular cell.

[138]  Raquel Herrador,et al.  Oncogenes induce genotoxic stress by mitotic processing of unusual replication intermediates , 2013, The Journal of cell biology.

[139]  Marco Foiani,et al.  Maintaining genome stability at the replication fork , 2010, Nature Reviews Molecular Cell Biology.

[140]  Michael A. Gonzalez,et al.  Control of DNA replication and its potential clinical exploitation , 2005, Nature Reviews Cancer.

[141]  L. Loeb,et al.  Human Werner Syndrome DNA Helicase Unwinds Tetrahelical Structures of the Fragile X Syndrome Repeat Sequence d(CGG) n * , 1999, The Journal of Biological Chemistry.

[142]  Junjie Chen,et al.  DNA damage tolerance: a double-edged sword guarding the genome. , 2013, Translational cancer research.

[143]  Reuven Agami,et al.  p53-Dependent Regulation of Cdc6 Protein Stability Controls Cellular Proliferation , 2005, Molecular and Cellular Biology.

[144]  T. Ørntoft,et al.  DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis , 2005, Nature.

[145]  T. Helleday,et al.  Hydroxyurea-Stalled Replication Forks Become Progressively Inactivated and Require Two Different RAD51-Mediated Pathways for Restart and Repair , 2010, Molecular cell.

[146]  T. Helleday,et al.  Increased replication initiation and conflicts with transcription underlie Cyclin E-induced replication stress , 2013, Oncogene.

[147]  Radhakrishnan Kanagaraj,et al.  Human RECQ5β helicase promotes strand exchange on synthetic DNA structures resembling a stalled replication fork , 2006, Nucleic acids research.

[148]  S. Beausoleil,et al.  Disrupting Protein NEDDylation with MLN4924 Is a Novel Strategy to Target Cisplatin Resistance in Ovarian Cancer , 2013, Clinical Cancer Research.

[149]  P. Pasero,et al.  The causes of replication stress and their consequences on genome stability and cell fate. , 2014, Seminars in cell & developmental biology.

[150]  K. Eckert,et al.  DNA polymerase kappa microsatellite synthesis: Two distinct mechanisms of slippage‐mediated errors , 2012, Environmental and molecular mutagenesis.

[151]  D. Lane,et al.  Cell type-specific responses of human cells to inhibition of replication licensing , 2002, Oncogene.

[152]  A. Davies,et al.  Ubiquitin-dependent DNA damage bypass is separable from genome replication , 2010, Nature.

[153]  A. Mazin,et al.  Cooperation of RAD51 and RAD54 in regression of a model replication fork , 2010, Nucleic acids research.

[154]  Andrzej Stasiak,et al.  The Fanconi anemia protein FANCM can promote branch migration of Holliday junctions and replication forks. , 2008, Molecular cell.

[155]  B. Eichman,et al.  Substrate-selective repair and restart of replication forks by DNA translocases. , 2013, Cell reports.

[156]  J. Gautier,et al.  Cdc45 is a critical effector of myc-dependent DNA replication stress. , 2013, Cell reports.

[157]  M. Lopes,et al.  FBH1 Catalyzes Regression of Stalled Replication Forks. , 2015, Cell reports.

[158]  B. Kerem,et al.  Nucleotide Deficiency Promotes Genomic Instability in Early Stages of Cancer Development , 2011, Cell.

[159]  Alan Ashworth,et al.  Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy , 2005, Nature.

[160]  J. Bartek,et al.  Functional interplay between the DNA-damage-response kinase ATM and ARF tumour suppressor protein in human cancer , 2013, Nature Cell Biology.

[161]  S. Sarkar,et al.  Inhibiting WEE1 Selectively Kills Histone H3K36me3-Deficient Cancers by dNTP Starvation , 2015, Cancer cell.

[162]  M. Lopes,et al.  DNA2 drives processing and restart of reversed replication forks in human cells , 2015, The Journal of cell biology.

[163]  A. Doherty,et al.  Human PrimPol mutation associated with high myopia has a DNA replication defect , 2014, Nucleic acids research.

[164]  A. Gartner,et al.  Excess Mcm2–7 license dormant origins of replication that can be used under conditions of replicative stress , 2006, The Journal of cell biology.