DNA repair pathways as targets for cancer therapy

DNA repair pathways can enable tumour cells to survive DNA damage that is induced by chemotherapeutic treatments; therefore, inhibitors of specific DNA repair pathways might prove efficacious when used in combination with DNA-damaging chemotherapeutic drugs. In addition, alterations in DNA repair pathways that arise during tumour development can make some cancer cells reliant on a reduced set of DNA repair pathways for survival. There is evidence that drugs that inhibit one of these pathways in such tumours could prove useful as single-agent therapies, with the potential advantage that this approach could be selective for tumour cells and have fewer side effects.

[1]  T. Helleday,et al.  Poly(ADP-ribose) Polymerase (PARP-1) in Homologous Recombination and as a Target for Cancer Therapy , 2005, Cell cycle.

[2]  S. Seal,et al.  Localization of a breast cancer susceptibility gene, BRCA2, to chromosome 13q12-13. , 1994, Science.

[3]  S. Loeillet,et al.  Links between replication and recombination in Saccharomyces cerevisiae: A hypersensitive requirement for homologous recombination in the absence of Rad27 activity , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[4]  S. Elledge,et al.  Identification of RNR4, encoding a second essential small subunit of ribonucleotide reductase in Saccharomyces cerevisiae , 1997, Molecular and cellular biology.

[5]  B. Sedgwick.  Repairing DNA-methylation damage , 2004, Nature Reviews Molecular Cell Biology.

[6]  Daniel Durocher,et al.  Elg1 Forms an Alternative PCNA-Interacting RFC Complex Required to Maintain Genome Stability , 2003, Current Biology.

[7]  N. Saijo,et al.  Participation of poly(ADP-robose) polymerase in the drug sensitivity in human lung cancer cell lines , 2005, Journal of Cancer Research and Clinical Oncology.

[8]  E. Passarge,et al.  Bloom's syndrome. V. Surveillance for cancer in affected families , 1977, Clinical genetics.

[9]  R. Rothstein,et al.  The ribonucleotide reductase inhibitor Sml1 is a new target of the Mec1/Rad53 kinase cascade during growth and in response to DNA damage , 2001, The EMBO journal.

[10]  T. Kunkel,et al.  Yeast DNA polymerase epsilon participates in leading-strand DNA replication. , 2007, Science.

[11]  Y Taya,et al.  Activation of the ATM kinase by ionizing radiation and phosphorylation of p53. , 1998, Science.

[12]  Stephen C. West,et al.  Poly(ADP-ribose)-binding zinc finger motifs in DNA repair/checkpoint proteins , 2008, Nature.

[13]  S. Banerjee,et al.  DNA polymerase beta mutations in human colorectal cancer. , 1992, Cancer research.

[14]  K. Sugasawa,et al.  A multistep damage recognition mechanism for global genomic nucleotide excision repair. , 2001, Genes & development.

[15]  M. Middleton,et al.  The therapeutic potential of O6-alkylguanine DNA alkyltransferase inhibitors , 2007, Expert opinion on investigational drugs.

[16]  P. Bates,et al.  Reversal of DNA alkylation damage by two human dioxygenases , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[17]  T. Ogawa,et al.  Xrs2p regulates Mre11p translocation to the nucleus and plays a role in telomere elongation and meiotic recombination. , 2004, Molecular biology of the cell.

[18]  Li Chen,et al.  The DNA repair protein Rad23 is a negative regulator of multi-ubiquitin chain assembly , 2000, Nature Cell Biology.

[19]  J. Cooper,et al.  Effect of hypoxia on DNA synthesis in the bone marrow and spleen of the rat. , 1954, Science.

[20]  Huiming Ding,et al.  A Snf2 family ATPase complex required for recruitment of the histone H2A variant Htz1. , 2003, Molecular cell.

[21]  Dimitris Kletsas,et al.  Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints , 2006, Nature.

[22]  K. Myung,et al.  The Rad1-Rad10 Complex Promotes the Production of Gross Chromosomal Rearrangements From Spontaneous DNA Damage in Saccharomyces cerevisiae , 2005, Genetics.

[23]  A. Tong,et al.  A Network of Multi-Tasking Proteins at the DNA Replication Fork Preserves Genome Stability , 2005, PLoS genetics.

[24]  A. Chapelle,et al.  Genetic predisposition to colorectal cancer , 2004, Nature Reviews Cancer.

[25]  D. Branzei,et al.  The product of Saccharomyces cerevisiae WHIP/MGS1, a gene related to replication factor C genes, interacts functionally with DNA polymerase δ , 2002, Molecular Genetics and Genomics.

[26]  I. M. Jones,et al.  Disparate contributions of the Fanconi anemia pathway and homologous recombination in preventing spontaneous mutagenesis , 2007, Nucleic acids research.

[27]  T. Helleday,et al.  Inhibition of poly (ADP-ribose) polymerase activates ATM which is required for subsequent homologous recombination repair , 2006, Nucleic acids research.

[28]  Alessandra Viel,et al.  Human MRE11 is inactivated in mismatch repair‐deficient cancers , 2002, EMBO reports.

[29]  J. R. Ferguson,et al.  The Nuclease Activity of Mre11 Is Required for Meiosis but Not for Mating Type Switching, End Joining, or Telomere Maintenance , 1999, Molecular and Cellular Biology.

[30]  A. Sancar,et al.  Human nucleotide excision nuclease removes thymine dimers from DNA by incising the 22nd phosphodiester bond 5' and the 6th phosphodiester bond 3' to the photodimer. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[31]  Eric F. Johnson,et al.  ABT-888, an Orally Active Poly(ADP-Ribose) Polymerase Inhibitor that Potentiates DNA-Damaging Agents in Preclinical Tumor Models , 2007, Clinical Cancer Research.

[32]  Karen H. Vousden,et al.  p53 in health and disease , 2007, Nature Reviews Molecular Cell Biology.

[33]  P. Reichard,et al.  Changes of deoxyribonucleoside triphosphate pools induced by hydroxyurea and their relation to DNA synthesis. , 1986, The Journal of biological chemistry.

[34]  F. Alt,et al.  Defective DNA-dependent protein kinase activity is linked to V(D)J recombination and DNA repair defects associated with the murine scid mutation , 1995, Cell.

[35]  P. Glazer,et al.  Regulation of DNA repair in hypoxic cancer cells , 2007, Cancer and Metastasis Reviews.

[36]  H. Jiang,et al.  Cell cycle checkpoint abrogator UCN-01 inhibits DNA repair: association with attenuation of the interaction of XPA and ERCC1 nucleotide excision repair proteins. , 1999, Cancer research.

[37]  A. Levine,et al.  The p53 tumour suppressor gene , 1991, Nature.

[38]  R. Barbey,et al.  Synergism between base excision repair, mediated by the DNA glycosylases Ntg1 and Ntg2, and nucleotide excision repair in the removal of oxidatively damaged DNA bases in Saccharomyces cerevisiae , 2001, Molecular Genetics and Genomics.

[39]  I. Hickson,et al.  DNA helicase deficiencies associated with cancer predisposition and premature ageing disorders. , 2001, Human molecular genetics.

[40]  K. Caldecott,et al.  Poly(ADP-Ribose) Polymerase 1 Accelerates Single-Strand Break Repair in Concert with Poly(ADP-Ribose) Glycohydrolase , 2007, Molecular and Cellular Biology.

[41]  R. Kolodner,et al.  A Novel Mutation Avoidance Mechanism Dependent on S. cerevisiae RAD27 Is Distinct from DNA Mismatch Repair , 1997, Cell.

[42]  M. Brenneman,et al.  Repair of site-specific double-strand breaks in a mammalian chromosome by homologous and illegitimate recombination , 1997, Molecular and cellular biology.

[43]  B. Ruggeri,et al.  Chemopotentiation of temozolomide, irinotecan, and cisplatin activity by CEP-6800, a poly(ADP-ribose) polymerase inhibitor. , 2003, Molecular cancer therapeutics.

[44]  S. West,et al.  Werner's syndrome protein (WRN) migrates Holliday junctions and co‐localizes with RPA upon replication arrest , 2000, EMBO reports.

[45]  Dimitris Kletsas,et al.  Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions , 2005, Nature.

[46]  Miki Ii,et al.  Roles of SGS1, MUS81, and RAD51 in the repair of lagging-strand replication defects in Saccharomyces cerevisiae , 2005, Current Genetics.

[47]  Liming Wang,et al.  DNA Polymerase β Mutations in Human Colorectal Cancer , 1992 .

[48]  Joseph,et al.  Topoisomerase I (-mediated DNA Breaks and Cytotoxicity in Relation to Cell Proliferation and the Cell Cycle in NIH 3 T 3 Fibroblasts and L 1210 Leukemia Cells , 2006 .

[49]  J. Bader,et al.  A robust toolkit for functional profiling of the yeast genome. , 2004, Molecular cell.

[50]  L. D. Barnes,et al.  Alterations in DNA repair and telomere maintenance mechanism affect response to porphyrins in yeast. , 2001, Anticancer research.

[51]  K. Erixon,et al.  Single-strand breaks in DNA during repair of UV-induced damage in normal human and xeroderma pigmentosum cells as determined by alkaline DNA unwinding and hydroxylapatite chromatography: effects of hydroxyurea, 5-fluorodeoxyuridine and 1-beta-D-arabinofuranosylcytosine on the kinetics of repair. , 1979, Mutation research.

[52]  A. Ui,et al.  Functional and physical interaction between Sgs1 and Top3 and Sgs1-independent function of Top3 in DNA recombination repair. , 2002, Genes & genetic systems.

[53]  M. Connelly,et al.  DNA-dependent protein kinase catalytic subunit: A relative of phosphatidylinositol 3-kinase and the ataxia telangiectasia gene product , 1995, Cell.

[54]  J. Cleaver,et al.  Repair Replication in HeLa Cells after Large Doses of X-irradiation , 1967, Nature.

[55]  J. Willson,et al.  Modulation of nitrosourea resistance in human colon cancer by O6-methylguanine. , 1992, Biochemical pharmacology.

[56]  G. Margison,et al.  Improvement of chemotherapy efficacy by inactivation of a DNA-repair pathway. , 2003, The Lancet. Oncology.

[57]  James E. Haber,et al.  Telomere maintenance is dependent on activities required for end repair of double-strand breaks , 1998, Current Biology.

[58]  Hans Joenje,et al.  Fanconi anemia and DNA replication repair. , 2007, DNA repair.

[59]  P. Jeggo,et al.  Identification of a defect in DNA ligase IV in a radiosensitive leukaemia patient , 1999, Current Biology.

[60]  T. Helleday,et al.  Inhibition of DNA synthesis is a potent mechanism by which cytostatic drugs induce homologous recombination in mammalian cells. , 2000, Mutation research.

[61]  S. Brill,et al.  The Mechanism of Mus81-Mms4 Cleavage Site Selection Distinguishes It from the Homologous Endonuclease Rad1-Rad10 , 2003, Molecular and Cellular Biology.

[62]  E. Winzeler,et al.  Coordinated functions of WSS1, PSY2 and TOF1 in the DNA damage response. , 2004, Nucleic acids research.

[63]  Robert Brown,et al.  The Acquisition of hMLH 1 Methylation in Plasma DNA after Chemotherapy Predicts Poor Survival for Ovarian Cancer Patients , 2004 .

[64]  E. Louis,et al.  SGS1 is required for telomere elongation in the absence of telomerase , 2001, Current Biology.

[65]  Elisabeth Brambilla,et al.  DNA repair by ERCC1 in non-small-cell lung cancer and cisplatin-based adjuvant chemotherapy. , 2006, The New England journal of medicine.

[66]  J. Blenis,et al.  Activation of pp70/85 S6 kinases in interleukin-2-responsive lymphoid cells is mediated by phosphatidylinositol 3-kinase and inhibited by cyclic AMP , 1995, Molecular and cellular biology.

[67]  L. Karnitz,et al.  Pharmacological Abrogation of S-Phase Checkpoint Enhances the Anti-Tumor Activity of Gemcitabine In Vivo , 2007, Cell cycle.

[68]  D. Hanahan,et al.  The Hallmarks of Cancer , 2000, Cell.

[69]  D. Gordenin,et al.  Destabilization of Yeast Micro- and Minisatellite DNA Sequences by Mutations Affecting a Nuclease Involved in Okazaki Fragment Processing (rad27) and DNA Polymerase δ (pol3-t) , 1998, Molecular and Cellular Biology.

[70]  R. Fleischmann,et al.  Mutations of two P/WS homologues in hereditary nonpolyposis colon cancer , 1994, Nature.

[71]  K. J. Patel,et al.  The Fanconi anaemia gene FANCC promotes homologous recombination and error-prone DNA repair. , 2004, Molecular cell.

[72]  H. Maki,et al.  Distinct roles of DNA polymerases delta and epsilon at the replication fork in Xenopus egg extracts , 2004, Genes to cells : devoted to molecular & cellular mechanisms.

[73]  M. Marinus,et al.  Mismatch correction at O6-methylguanine residues in E. coli DNA , 1982, Nature.

[74]  P. Wipf,et al.  Chemistry and biology of wortmannin. , 2005, Organic & biomolecular chemistry.

[75]  M. Ranson,et al.  Lomeguatrib, a Potent Inhibitor of O6-Alkylguanine-DNA-Alkyltransferase: Phase I Safety, Pharmacodynamic, and Pharmacokinetic Trial and Evaluation in Combination with Temozolomide in Patients with Advanced Solid Tumors , 2006, Clinical Cancer Research.

[76]  P. Hsieh,et al.  ATR kinase activation mediated by MutSalpha and MutLalpha in response to cytotoxic O6-methylguanine adducts. , 2006, Molecular cell.

[77]  B. Ponder,et al.  Involvement of Brca2 in DNA repair. , 1998, Molecular cell.

[78]  M. Tyers,et al.  The F-Box Protein Dia2 Overcomes Replication Impedance to Promote Genome Stability in Saccharomyces cerevisiae , 2006, Genetics.

[79]  R. Mirimanoff,et al.  Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. , 2005, The New England journal of medicine.

[80]  L. Symington.  Homologous recombination is required for the viability of rad27 mutants. , 1998, Nucleic acids research.

[81]  J. Wallis,et al.  A hyper-recombination mutation in S. cerevisiae identifies a novel eukaryotic topoisomerase , 1989, Cell.

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

[83]  A. Fischer,et al.  Partial T and B lymphocyte immunodeficiency and predisposition to lymphoma in patients with hypomorphic mutations in Artemis. , 2003, The Journal of clinical investigation.

[84]  K. Ohta,et al.  Ubc9- and Mms21-Mediated Sumoylation Counteracts Recombinogenic Events at Damaged Replication Forks , 2006, Cell.

[85]  R. Chanet,et al.  Characterization of mutations that are synthetic lethal with pol3-13, a mutated allele of DNA polymerase delta in Saccharomyces cerevisiae , 2003, Current Genetics.

[86]  F. Collins,et al.  Germline and somatic mutation analyses in the DNA mismatch repair gene MLH3: Evidence for somatic mutation in colorectal cancers , 2001, Human mutation.

[87]  K. Kinzler,et al.  Genetic instabilities in human cancers , 1998, Nature.

[88]  Tim J. Craig,et al.  SGS1 is a multicopy suppressor of srs2: functional overlap between DNA helicases. , 2002, Nucleic Acids Research.

[89]  Zhao-Qi Wang,et al.  Ablation of PARP-1 does not interfere with the repair of DNA double-strand breaks, but compromises the reactivation of stalled replication forks , 2004, Oncogene.

[90]  W. V. D. Van de Ven,et al.  Allelic knockout of novel splice variants of human recombination repair gene RAD51B in t(12;14) uterine leiomyomas. , 1999, Cancer research.

[91]  D. Lin,et al.  Fen1 mutations result in autoimmunity, chronic inflammation and cancers , 2007, Nature Medicine.

[92]  Li Chen,et al.  Pleiotropic defects caused by loss of the proteasome-interacting factors Rad23 and Rpn10 of Saccharomyces cerevisiae. , 1999, Genetics.

[93]  G. Lucchini,et al.  Sudden telomere lengthening triggers a Rad53-dependent checkpoint in Saccharomyces cerevisiae. , 2003, Molecular biology of the cell.

[94]  A. Giaccia,et al.  Inhibition of ATR Leads to Increased Sensitivity to Hypoxia/Reoxygenation , 2004, Cancer Research.

[95]  S. Schreiber,et al.  Overexpression of a kinase‐inactive ATR protein causes sensitivity to DNA‐damaging agents and defects in cell cycle checkpoints , 1998, The EMBO journal.

[96]  Robert Brown,et al.  The Acquisition of hMLH1 Methylation in Plasma DNA after Chemotherapy Predicts Poor Survival for Ovarian Cancer Patients , 2004, Clinical Cancer Research.

[97]  J. Sludden,et al.  Reversal of drug resistance in human tumor xenografts by 2'-deoxy-5-azacytidine-induced demethylation of the hMLH1 gene promoter. , 2000, Cancer research.

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

[99]  I. Hickson,et al.  DNA helicases required for homologous recombination and repair of damaged replication forks. , 2006, Annual review of genetics.

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

[101]  G. Thomas,et al.  [Genetic predisposition to colorectal cancer]. , 1993, Annales de gastroenterologie et d'hepatologie.

[102]  D. Bentley,et al.  Identification of the breast cancer susceptibility gene BRCA2 , 1995, Nature.

[103]  Marc P. Waase,et al.  Analysis of conditional mutations in the Saccharomyces cerevisiae MLH1 gene in mismatch repair and in meiotic crossing over. , 2002, Genetics.

[104]  Kristopher H. McConnell,et al.  A Dbf4p BRCA1 C-Terminal-Like Domain Required for the Response to Replication Fork Arrest in Budding Yeast , 2006, Genetics.

[105]  Hiroki Inui,et al.  Mutations of a novel human RAD54 homologue, RAD54B, in primary cancer , 1999, Oncogene.

[106]  T. Helleday,et al.  DNA double-strand breaks associated with replication forks are predominantly repaired by homologous recombination involving an exchange mechanism in mammalian cells. , 2001, Journal of molecular biology.

[107]  Huiming Ding,et al.  The synthetic genetic interaction spectrum of essential genes , 2005, Nature Genetics.

[108]  P. Norris,et al.  Xeroderma pigmentosum complementation group F in a non-Japanese patient. , 1988, Journal of the American Academy of Dermatology.

[109]  JAMES C. Wang,et al.  Cellular roles of DNA topoisomerases: a molecular perspective , 2002, Nature Reviews Molecular Cell Biology.

[110]  D. Burke,et al.  Diverse Functions of Spindle Assembly Checkpoint Genes in Saccharomyces cerevisiae , 2006, Genetics.

[111]  C. Schmitt.  Senescence, apoptosis and therapy — cutting the lifelines of cancer , 2003, Nature Reviews Cancer.

[112]  I. Hardcastle,et al.  Identification of a highly potent and selective DNA-dependent protein kinase (DNA-PK) inhibitor (NU7441) by screening of chromenone libraries. , 2004, Bioorganic & medicinal chemistry letters.

[113]  N. Curtin,et al.  Preclinical evaluation of a potent novel DNA-dependent protein kinase inhibitor NU7441. , 2006, Cancer research.

[114]  A. Giaccia,et al.  ATR/ATM Targets Are Phosphorylated by ATR in Response to Hypoxia and ATM in Response to Reoxygenation* , 2003, The Journal of Biological Chemistry.

[115]  Serge Boiteux,et al.  Use of yeast for detection of endogenous abasic lesions, their source, and their repair. , 2006, Methods in enzymology.

[116]  J. Cleaver.  Cancer in xeroderma pigmentosum and related disorders of DNA repair , 2005, Nature Reviews Cancer.

[117]  E. Alani,et al.  Characterization of the repeat-tract instability and mutator phenotypes conferred by a Tn3 insertion in RFC1, the large subunit of the yeast clamp loader. , 1999, Genetics.

[118]  G. Faye,et al.  Oxygen metabolism and reactive oxygen species cause chromosomal rearrangements and cell death , 2007, Proceedings of the National Academy of Sciences.

[119]  G. Faye,et al.  The KIN28 gene is required both for RNA polymerase II mediated transcription and phosphorylation of the Rpb1p CTD. , 1995, Journal of molecular biology.

[120]  T. Sokolsky,et al.  EXO1 and MSH6 are high-copy suppressors of conditional mutations in the MSH2 mismatch repair gene of Saccharomyces cerevisiae. , 2000, Genetics.

[121]  Judith L Campbell,et al.  Contribution of Trf4/5 and the Nuclear Exosome to Genome Stability Through Regulation of Histone mRNA Levels in Saccharomyces cerevisiae , 2007, Genetics.

[122]  K. Kohn,et al.  Topoisomerase II-mediated DNA breaks and cytotoxicity in relation to cell proliferation and the cell cycle in NIH 3T3 fibroblasts and L1210 leukemia cells. , 1987, Cancer research.

[123]  S. Brill,et al.  Requirement for three novel protein complexes in the absence of the Sgs1 DNA helicase in Saccharomyces cerevisiae. , 2001, Genetics.

[124]  T. Kunkel,et al.  The 3′→5′ exonuclease of DNA polymerase δ can substitute for the 5′ flap endonuclease Rad27/Fen1 in processing Okazaki fragments and preventing genome instability , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[125]  M. Marinus,et al.  Mismatch repair of cis-diamminedichloroplatinum(II)-induced DNA damage. , 1985, Molecular pharmacology.

[126]  T. Weitao,et al.  Evidence that yeast SGS1, DNA2, SRS2, and FOB1 interact to maintain rDNA stability. , 2003, Mutation research.

[127]  P. Møller,et al.  Familial endometrial cancer in female carriers of MSH6 germline mutations , 1999, Nature Genetics.

[128]  Jiri Bartek,et al.  Cell-cycle checkpoints and cancer , 2004, Nature.

[129]  Jiri Bartek,et al.  The cell-cycle checkpoint kinase Chk1 is required for mammalian homologous recombination repair , 2005, Nature Cell Biology.

[130]  T. Lindahl,et al.  Suicide inactivation of the E. coli O6‐methylguanine‐DNA methyltransferase. , 1982, The EMBO journal.

[131]  Steven E. Bayer,et al.  A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. , 1994, Science.

[132]  Gary D Bader,et al.  Global Mapping of the Yeast Genetic Interaction Network , 2004, Science.

[133]  F. Fabre,et al.  Alternate pathways involving Sgs1/Top3, Mus81/ Mms4, and Srs2 prevent formation of toxic recombination intermediates from single-stranded gaps created by DNA replication , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[134]  R. Wellinger,et al.  A mutation in yeast Tel1p that causes differential effects on the DNA damage checkpoint and telomere maintenance , 2005, Current Genetics.

[135]  P. Hsieh,et al.  ATR Kinase Activation Mediated by MutSα and MutLα in Response to Cytotoxic O6-Methylguanine Adducts , 2006 .

[136]  V. Zakian,et al.  Saccharomyces cerevisiae Rrm3p DNA Helicase Promotes Genome Integrity by Preventing Replication Fork Stalling: Viability of rrm3 Cells Requires the Intra-S-Phase Checkpoint and Fork Restart Activities , 2004, Molecular and Cellular Biology.

[137]  M. Mark,et al.  Early Embryonic Lethality in PARP-1 AtmDouble-Mutant Mice Suggests a Functional Synergy in Cell Proliferation during Development , 2001, Molecular and Cellular Biology.

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

[139]  S. Murakami,et al.  STM1, a gene which encodes a guanine quadruplex binding protein, interacts with CDC13 in Saccharomyces cerevisiae , 2002, Molecular Genetics and Genomics.

[140]  P. Glazer,et al.  Genetic instability induced by the tumor microenvironment. , 1996, Cancer research.

[141]  T. Helleday,et al.  Homologous recombination is involved in repair of chromium-induced DNA damage in mammalian cells. , 2006, Mutation research.

[142]  H. Stein,et al.  Oncogene-induced senescence as an initial barrier in lymphoma development , 2005, Nature.

[143]  D. Branzei,et al.  Mgs1 and Rad18/Rad5/Mms2 are required for survival of Saccharomyces cerevisiae mutants with novel temperature/cold sensitive alleles of the DNA polymerase delta subunit, Pol31. , 2006, DNA repair.

[144]  Oscar M. Aparicio,et al.  Diminished S-Phase Cyclin-Dependent Kinase Function Elicits Vital Rad53-Dependent Checkpoint Responses in Saccharomyces cerevisiae , 2004, Molecular and Cellular Biology.

[145]  L. Hartwell,et al.  The Saccharomyces cerevisiae RAD9, RAD17, RAD24 and MEC3 genes are required for tolerating irreparable, ultraviolet-induced DNA damage. , 1998, Genetics.

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

[147]  Alan Ashworth,et al.  Deficiency in the repair of DNA damage by homologous recombination and sensitivity to poly(ADP-ribose) polymerase inhibition. , 2006, Cancer research.

[148]  J. German.  Bloom's syndrome , 1995 .

[149]  F. Cross,et al.  Disruption of Mechanisms That Prevent Rereplication Triggers a DNA Damage Response , 2005, Molecular and Cellular Biology.

[150]  F. Hanaoka,et al.  Efficient translesion replication past oxaliplatin and cisplatin GpG adducts by human DNA polymerase eta. , 2000, Biochemistry.

[151]  L. Thompson,et al.  Strategies for cloning mammalian DNA repair genes. , 1999, Methods in molecular biology.

[152]  M. Dyer,et al.  Clustering of missense mutations in the ataxia-telanglectasia gene in a sporadic T-cell leukaemia , 1997, Nature Genetics.

[153]  M. Dolan,et al.  O6-benzylguanine and its role in chemotherapy. , 1997, Clinical cancer research : an official journal of the American Association for Cancer Research.

[154]  G. Dianov,et al.  Targeting base excision repair to improve cancer therapies. , 2007, Molecular aspects of medicine.

[155]  L. Liu,et al.  Arrest of replication forks by drug-stabilized topoisomerase I-DNA cleavable complexes as a mechanism of cell killing by camptothecin. , 1989, Cancer research.

[156]  A. Lehmann.  Translesion synthesis in mammalian cells. , 2006, Experimental cell research.

[157]  R. Kanaar,et al.  The structure-specific endonuclease Mus81 contributes to replication restart by generating double-strand DNA breaks , 2007, Nature Structural &Molecular Biology.

[158]  P. Tran,et al.  Characterization of nuclease-dependent functions of Exo1p in Saccharomyces cerevisiae. , 2002, DNA repair.

[159]  Erica S. Johnson,et al.  Topoisomerase I-Dependent Viability Loss in Saccharomyces cerevisiae Mutants Defective in Both SUMO Conjugation and DNA Repair , 2007, Genetics.

[160]  J. Lieberman,et al.  A phosphatase complex that dephosphorylates γH2AX regulates DNA damage checkpoint recovery , 2006, Nature.

[161]  G. C. Johnston,et al.  The Gcs1 Arf-GAP mediates Snc1,2 v-SNARE retrieval to the Golgi in yeast. , 2006, Molecular biology of the cell.

[162]  A. V. D. Eb,et al.  A presumed DNA helicase encoded by ERCC-3 is involved in the human repair disorders xeroderma pigmentosum and Cockayne's syndrome , 1990, Cell.

[163]  K. Isselbacher,et al.  Heterozygous germ line hCHK2 mutations in Li-Fraumeni syndrome. , 1999, Science.

[164]  Sean V Tavtigian,et al.  Characterization of a carboxy-terminal BRCA1 interacting protein , 1998, Oncogene.

[165]  H. Klein.  Mutations in recombinational repair and in checkpoint control genes suppress the lethal combination of srs2Delta with other DNA repair genes in Saccharomyces cerevisiae. , 2001, Genetics.

[166]  F. Cross,et al.  Mutations in RAD27 define a potential link between G1 cyclins and DNA replication , 1995, Molecular and cellular biology.

[167]  J. Trosko,et al.  Platinum Compounds: a New Class of Potent Antitumour Agents , 1969, Nature.

[168]  R. Fleischmann,et al.  Mutation of a mutL homolog in hereditary colon cancer. , 1994, Science.

[169]  K. Kinzler,et al.  Cancer-susceptibility genes. Gatekeepers and caretakers. , 1997, Nature.

[170]  T. Helleday,et al.  Poly(ADP-ribose) polymerase (PARP-1) has a controlling role in homologous recombination. , 2003, Nucleic acids research.

[171]  S. Gibson,et al.  Hypoxia-induced phosphorylation of Chk2 in an ataxia telangiectasia mutated-dependent manner. , 2005, Cancer research.

[172]  A. Yasui,et al.  Analysis of a human DNA excision repair gene involved in group A xeroderma pigmentosum and containing a zinc-finger domain , 1990, Nature.

[173]  B. Chabner,et al.  Chemotherapy and the war on cancer , 2005, Nature Reviews Cancer.

[174]  Charles Boone,et al.  RMI1/NCE4, a suppressor of genome instability, encodes a member of the RecQ helicase/Topo III complex , 2005 .

[175]  P. Leder,et al.  The Werner Syndrome Gene Product Co-purifies with the DNA Replication Complex and Interacts with PCNA and Topoisomerase I* , 1999, The Journal of Biological Chemistry.

[176]  S. Elledge,et al.  Asf1 links Rad53 to control of chromatin assembly. , 2001, Genes & development.

[177]  Charles Boone,et al.  Synthetic lethal analysis implicates Ste20p, a p21-activated potein kinase, in polarisome activation. , 2003, Molecular biology of the cell.

[178]  P. Russell,et al.  Human Mus81-associated endonuclease cleaves Holliday junctions in vitro. , 2001, Molecular cell.

[179]  M. Jasin,et al.  BRCA2 is required for homology-directed repair of chromosomal breaks. , 2001, Molecular cell.

[180]  M. Hoekstra,et al.  Relationships between a hyper-rec mutation (REM1) and other recombination and repair genes in yeast. , 1984, Genetics.

[181]  F. Fabre,et al.  Homologous recombination is responsible for cell death in the absence of the Sgs1 and Srs2 helicases , 2000, Nature Genetics.

[182]  Qinguo Zheng,et al.  Role of Postreplicative DNA Mismatch Repair in the Cytotoxic Action of Thioguanine , 1996, Science.

[183]  N. Mailand,et al.  The ATM–Chk2–Cdc25A checkpoint pathway guards against radioresistant DNA synthesis , 2001, Nature.

[184]  F. Hanaoka,et al.  Mechanisms of accurate translesion synthesis by human DNA polymerase η , 2000, The EMBO journal.

[185]  M. Dolan,et al.  Molecular mechanisms of resistance and toxicity associated with platinating agents. , 2007, Cancer treatment reviews.

[186]  Ian D. Hickson,et al.  The Bloom's syndrome helicase suppresses crossing over during homologous recombination , 2003, Nature.

[187]  S P Langdon,et al.  Antitumor activity and pharmacokinetics in mice of 8-carbamoyl-3-methyl-imidazo[5,1-d]-1,2,3,5-tetrazin-4(3H)-one (CCRG 81045; M & B 39831), a novel drug with potential as an alternative to dacarbazine. , 1987, Cancer research.

[188]  S. Linn,et al.  Mutations Specific to the Xeroderma Pigmentosum Group E Ddb− Phenotype* , 1996, The Journal of Biological Chemistry.

[189]  R. Sclafani,et al.  RAD53 regulates DBF4 independently of checkpoint function in Saccharomyces cerevisiae. , 1999, Genetics.

[190]  R. Chanet,et al.  A New Saccharomyces cerevisiae Strain with a Mutant Smt3-Deconjugating Ulp1 Protein Is Affected in DNA Replication and Requires Srs2 and Homologous Recombination for Its Viability , 2004, Molecular and Cellular Biology.

[191]  D. Garfinkel,et al.  Nucleotide Excision Repair/TFIIH Helicases Rad3 and Ssl2 Inhibit Short-Sequence Recombination and Ty1 Retrotransposition by Similar Mechanisms , 2000, Molecular and Cellular Biology.

[192]  B. Koller,et al.  Brca1 controls homology-directed DNA repair. , 1999, Molecular cell.

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

[194]  Gary D Bader,et al.  Systematic Genetic Analysis with Ordered Arrays of Yeast Deletion Mutants , 2001, Science.

[195]  A. Taylor,et al.  Ataxia telangiectasia: a human mutation with abnormal radiation sensitivity , 1975, Nature.

[196]  J. Nickoloff,et al.  Sgs1 Regulates Gene Conversion Tract Lengths and Crossovers Independently of Its Helicase Activity , 2006, Molecular and Cellular Biology.

[197]  T. Helleday,et al.  DNA double-strand break repair: from mechanistic understanding to cancer treatment. , 2007, DNA repair.

[198]  R. Schimke,et al.  Gene amplification in a single cell cycle in Chinese hamster ovary cells. , 1984, The Journal of biological chemistry.

[199]  M. Spitz,et al.  Expression of nucleotide excision repair genes and the risk for squamous cell carcinoma of the head and neck , 2002, Cancer.

[200]  B. Dujon,et al.  Genetic network interactions among replication, repair and nuclear pore deficiencies in yeast. , 2005, DNA repair.

[201]  M. Mehta,et al.  Phase I trial of intravenous thymidine and carboplatin in patients with advanced cancer. , 1999, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[202]  S. Brill,et al.  Role of SGS1 and SLX4 in maintaining rDNA structure in Saccharomyces cerevisiae , 2002, Current Genetics.

[203]  J. Arrand,et al.  Molecular cloning and characterization of a mammalian excision repair gene that partially restores UV resistance to xeroderma pigmentosum complementation group D cells. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[204]  T. Kunkel,et al.  Yeast DNA Polymerase ε Participates in Leading-Strand DNA Replication , 2007, Science.

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

[206]  S. West,et al.  The Bloom's syndrome gene product promotes branch migration of holliday junctions. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[207]  L. Johnston,et al.  Pathway correcting DNA replication errors in Saccharomyces cerevisiae. , 1993, The EMBO journal.

[208]  Daniel A. Koster,et al.  Antitumour drugs impede DNA uncoiling by topoisomerase I , 2007, Nature.

[209]  S. Gangloff,et al.  Mutations in homologous recombination genes rescue top3 slow growth in Saccharomyces cerevisiae. , 2002, Genetics.

[210]  T. E. Wilson,et al.  Abrogation of the Chk1-Pds1 Checkpoint Leads to Tolerance of Persistent Single-Strand Breaks in Saccharomyces cerevisiae , 2005, Genetics.

[211]  Charles Boone,et al.  Elg1 forms an alternative RFC complex important for DNA replication and genome integrity , 2003, The EMBO journal.

[212]  A. Venkitaraman,et al.  Stabilization of stalled DNA replication forks by the BRCA2 breast cancer susceptibility protein. , 2003, Genes & development.

[213]  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.

[214]  Yusuke Nakamura,et al.  Positional cloning of the gene for Nijmegen breakage syndrome , 1998, Nature Genetics.

[215]  A. Giaccia,et al.  Hypoxia Links ATR and p53 through Replication Arrest , 2002, Molecular and Cellular Biology.

[216]  Andrew Emili,et al.  Navigating the Chaperone Network: An Integrative Map of Physical and Genetic Interactions Mediated by the Hsp90 Chaperone , 2005, Cell.

[217]  L. Seymour,et al.  Prognostic and predictive importance of p53 and RAS for adjuvant chemotherapy in non small-cell lung cancer. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[218]  Robert E. Johnson,et al.  hRAD30 mutations in the variant form of xeroderma pigmentosum. , 1999, Science.

[219]  H. Ogawa,et al.  Regulation of homologous integration in yeast by the DNA repair proteins Ku70 and RecQ , 2005, Molecular Genetics and Genomics.

[220]  N. Copeland,et al.  The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer , 1993, Cell.

[221]  R. Rothstein,et al.  The Absence of Top3 Reveals an Interaction Between the Sgs1 and Pif1 DNA Helicases in Saccharomyces cerevisiae , 2006, Genetics.

[222]  A. D’Andrea,et al.  Molecular pathogenesis of Fanconi anemia: recent progress. , 2006, Blood.

[223]  B. Durkacz,et al.  (ADP-ribose)n participates in DNA excision repair , 1980, Nature.

[224]  F. d’Adda di Fagagna,et al.  Breaking news: high-speed race ends in arrest--how oncogenes induce senescence. , 2007, Trends in cell biology.

[225]  R. McLendon,et al.  Phase I trial of temozolomide plus O6-benzylguanine for patients with recurrent or progressive malignant glioma. , 2000, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[226]  K. Tanaka,et al.  Purification and cloning of a nucleotide excision repair complex involving the xeroderma pigmentosum group C protein and a human homologue of yeast RAD23. , 1994, The EMBO journal.

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

[228]  P. Glazer,et al.  Genomic instability in cancer. , 2001, Novartis Foundation symposium.

[229]  Lei Li,et al.  Sensitivity to Phosphonoacetic Acid , 2005, Genetics.

[230]  J. Boeke,et al.  DNA helicase gene interaction network defined using synthetic lethality analyzed by microarray , 2003, Nature Genetics.

[231]  H. Klein.  Spontaneous chromosome loss in Saccharomyces cerevisiae is suppressed by DNA damage checkpoint functions. , 2001, Genetics.

[232]  M. Tischkowitz,et al.  Fanconi anaemia and leukaemia – clinical and molecular aspects , 2004, British journal of haematology.

[233]  Robert E. Johnson,et al.  Requirement of yeast SGS1 and SRS2 genes for replication and transcription. , 1999, Science.