DNA Double-Strand Break Repair as Determinant of Cellular Radiosensitivity to Killing and Target in Radiation Therapy

Radiation therapy plays an important role in the management of a wide range of cancers. Besides innovations in the physical application of radiation dose, radiation therapy is likely to benefit from novel approaches exploiting differences in radiation response between normal and tumor cells. While ionizing radiation induces a variety of DNA lesions, including base damages and single-strand breaks, the DNA double-strand break (DSB) is widely considered as the lesion responsible not only for the aimed cell killing of tumor cells, but also for the general genomic instability that leads to the development of secondary cancers among normal cells. Homologous recombination repair (HRR), non-homologous end-joining (NHEJ), and alternative NHEJ, operating as a backup, are the major pathways utilized by cells for the processing of DSBs. Therefore, their function represents a major mechanism of radiation resistance in tumor cells. HRR is also required to overcome replication stress – a potent contributor to genomic instability that fuels cancer development. HRR and alternative NHEJ show strong cell-cycle dependency and are likely to benefit from radiation therapy mediated redistribution of tumor cells throughout the cell-cycle. Moreover, the synthetic lethality phenotype documented between HRR deficiency and PARP inhibition has opened new avenues for targeted therapies. These observations make HRR a particularly intriguing target for treatments aiming to improve the efficacy of radiation therapy. Here, we briefly describe the major pathways of DSB repair and review their possible contribution to cancer cell radioresistance. Finally, we discuss promising alternatives for targeting DSB repair to improve radiation therapy and cancer treatment.

[1]  B. Biesecker,et al.  Breast cancer susceptibility genes. BRCA1 and BRCA2. , 1998, Medicine.

[2]  H. Klein,et al.  The consequences of Rad51 overexpression for normal and tumor cells. , 2008, DNA repair.

[3]  T. Helleday,et al.  The role of RAD51 in etoposide (VP16) resistance in small cell lung cancer , 2003, International journal of cancer.

[4]  L. Symington,et al.  Break-induced replication: What is it and what is it for? , 2008, Cell cycle.

[5]  T. Skorski,et al.  Targeting RAD 51 phosphotyrosine-315 to prevent unfaithful recombination repair in BCR-ABL 1 leukemia , 2011 .

[6]  J. Guirouilh-Barbat,et al.  Initiation of DNA double strand break repair: signaling and single-stranded resection dictate the choice between homologous recombination, non-homologous end-joining and alternative end-joining. , 2012, American journal of cancer research.

[7]  K. Hofmann,et al.  Inhibition of homologous recombination by the PCNA-interacting protein PARI. , 2012, Molecular cell.

[8]  Peter Bouwman,et al.  BRCA1 RING function is essential for tumor suppression but dispensable for therapy resistance. , 2011, Cancer cell.

[9]  T. Skorski Genetic Mechanisms of Chronic Myeloid Leukemia Blastic Transformation , 2012, Current Hematologic Malignancy Reports.

[10]  B. Reina-San-Martin,et al.  Parp1 facilitates alternative NHEJ, whereas Parp2 suppresses IgH/c-myc translocations during immunoglobulin class switch recombination , 2009, The Journal of experimental medicine.

[11]  M. Jasin Homologous repair of DNA damage and tumorigenesis:the BRCA connection , 2002, Oncogene.

[12]  A. Bürkle,et al.  Trans-dominant inhibition of poly(ADP-ribosyl)ation potentiates alkylation-induced shuttle-vector mutagenesis in Chinese hamster cells , 1999, Molecular and Cellular Biochemistry.

[13]  S. Kowalczykowski,et al.  BRCA2: Shining light on the regulation of DNA-binding selectivity by RAD51 , 2009, Cell cycle.

[14]  R. Kanaar,et al.  Brca2 (XRCC11) Deficiency Results in Radioresistant DNA Synthesis and a Higher Frequency of Spontaneous Deletions , 2002, Molecular and Cellular Biology.

[15]  R. Muschel,et al.  The novel ATR inhibitor VE-821 increases sensitivity of pancreatic cancer cells to radiation and chemotherapy , 2012, Cancer biology & therapy.

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

[17]  G. Baldini,et al.  Studies on the Mode of Ku Interaction with DNA* , 2002, The Journal of Biological Chemistry.

[18]  F. Alt,et al.  Robust chromosomal DNA repair via alternative end-joining in the absence of X-ray repair cross-complementing protein 1 (XRCC1) , 2012, Proceedings of the National Academy of Sciences.

[19]  D. Ramsden,et al.  Ku is a 5'dRP/AP lyase that excises nucleotide damage near broken ends , 2010, Nature.

[20]  S. Jackson,et al.  DNA helicases Sgs1 and BLM promote DNA double-strand break resection. , 2008, Genes & development.

[21]  D. Baltimore,et al.  Ataxia telangiectasia mutant protein activates c-Abl tyrosine kinase in response to ionizing radiation , 1997, Nature.

[22]  V. Guacci,et al.  Sister chromatid cohesion: a simple concept with a complex reality. , 2008, Annual review of cell and developmental biology.

[23]  Jonathan Maybaum,et al.  Mechanism of radiosensitization by the Chk1/2 inhibitor AZD7762 involves abrogation of the G2 checkpoint and inhibition of homologous recombinational DNA repair. , 2010, Cancer research.

[24]  T. Skorski,et al.  BCR/ABL oncogenic kinase promotes unfaithful repair of the reactive oxygen species-dependent DNA double-strand breaks. , 2004, Blood.

[25]  G. Iliakis,et al.  Extensive Repair of DNA Double-Strand Breaks in Cells Deficient in the DNA-PK-Dependent Pathway of NHEJ after Exclusion of Heat-Labile Sites , 2009, Radiation research.

[26]  G. Mufti,et al.  Increased error-prone NHEJ activity in myeloid leukemias is associated with DNA damage at sites that recruit key nonhomologous end-joining proteins. , 2003, Cancer research.

[27]  George Iliakis,et al.  PARP-1 and Ku compete for repair of DNA double strand breaks by distinct NHEJ pathways , 2006, Nucleic acids research.

[28]  S. Varambally,et al.  Mechanisms of enhanced radiation response following epidermal growth factor receptor signaling inhibition by erlotinib (Tarceva). , 2005, Cancer research.

[29]  H. Groen,et al.  Selective targeting of homologous DNA recombination repair by gemcitabine. , 2003, International journal of radiation oncology, biology, physics.

[30]  W. Sakai,et al.  The Epistatic Relationship between BRCA2 and the Other RAD51 Mediators in Homologous Recombination , 2011, PLoS genetics.

[31]  F. Alt,et al.  Mre11: roles in DNA repair beyond homologous recombination , 2009, Nature Structural &Molecular Biology.

[32]  R. Bristow,et al.  The receptor tyrosine kinase inhibitor amuvatinib (MP470) sensitizes tumor cells to radio- and chemo-therapies in part by inhibiting homologous recombination. , 2011, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[33]  S. Powell,et al.  BRCA1 and BRCA2: different roles in a common pathway of genome protection , 2011, Nature Reviews Cancer.

[34]  D. Livingston,et al.  BRCA1 and BRCA2: breast/ovarian cancer susceptibility gene products and participants in DNA double-strand break repair. , 2010, Carcinogenesis.

[35]  Samuel Hellman,et al.  Advances in radiotherapy and implications for the next century: a historical perspective. , 2009, Cancer research.

[36]  Martin Kupiec,et al.  New insights into the mechanism of homologous recombination in yeast. , 2004, Mutation research.

[37]  S. West,et al.  Holliday junction resolution in human cells: two junction endonucleases with distinct substrate specificities , 2002, The EMBO journal.

[38]  Ken‐ichi Yamamoto,et al.  Detection of c‐Abl kinase‐promoted phosphorylation of Rad51 by specific antibodies reveals that Y54 phosphorylation is dependent on that of Y315 , 2009, FEBS letters.

[39]  Y. Nishimune,et al.  Cell cycle-dependent expression of the mouseRad51 gene in proliferating cells , 1996, Molecular and General Genetics MGG.

[40]  Jiri Bartek,et al.  Human CtIP promotes DNA end resection , 2007, Nature.

[41]  P. Sung,et al.  Regulation of Rad51 Function by c-Abl in Response to DNA Damage* , 1998, The Journal of Biological Chemistry.

[42]  Barbara Corneo,et al.  Rag mutations reveal robust alternative end joining , 2007, Nature.

[43]  P. Pharoah,et al.  Increased frequency of TP53 mutations in BRCA1 and BRCA2 ovarian tumours , 1999, Genes, chromosomes & cancer.

[44]  S. B. Buonomo,et al.  53BP1 Regulates DSB Repair Using Rif1 to Control 5′ End Resection , 2013, Science.

[45]  Eleni P. Mimitou,et al.  Sae2, Exo1 and Sgs1 collaborate in DNA double-strand break processing , 2008, Nature.

[46]  J. Peters,et al.  Sister chromatid cohesion. , 2012, Cold Spring Harbor perspectives in biology.

[47]  P. Huertas,et al.  DNA resection in eukaryotes: deciding how to fix the break , 2010, Nature Structural &Molecular Biology.

[48]  Shunichi Takeda,et al.  Differential usage of non-homologous end-joining and homologous recombination in double strand break repair. , 2006, DNA repair.

[49]  D. Huo,et al.  SUMO Modification Regulates BLM and RAD51 Interaction at Damaged Replication Forks , 2009, PLoS biology.

[50]  J. Petrini,et al.  The MRE11 complex: starting from the ends , 2011, Nature Reviews Molecular Cell Biology.

[51]  S. Freier,et al.  Elevated levels of Rad51 recombination protein in tumor cells. , 2002, Cancer research.

[52]  G. Iliakis,et al.  Inhibition of B-NHEJ in plateau-phase cells is not a direct consequence of suppressed growth factor signaling. , 2012, International journal of radiation oncology, biology, physics.

[53]  C. Jaulin,et al.  Cell cycle regulation of the endogenous wild type Bloom's syndrome DNA helicase , 2000, Oncogene.

[54]  S. Lambert,et al.  Overexpression of mammalian Rad51 does not stimulate tumorigenesis while a dominant-negative Rad51 affects centrosome fragmentation, ploidy and stimulates tumorigenesis, in p53-defective CHO cells , 2003, Oncogene.

[55]  P. Russell,et al.  Context Dependence of Checkpoint Kinase 1 as a Therapeutic Target for Pancreatic Cancers Deficient in the BRCA2 Tumor Suppressor , 2011, Molecular Cancer Therapeutics.

[56]  David J. Chen,et al.  The Epidermal Growth Factor Receptor: A Role in Repair of Radiation-Induced DNA Damage , 2007, Clinical Cancer Research.

[57]  S. Keeney,et al.  Meiosis-Specific DNA Double-Strand Breaks Are Catalyzed by Spo11, a Member of a Widely Conserved Protein Family , 1997, Cell.

[58]  A. Tomkinson,et al.  Eukaryotic DNA ligases: structural and functional insights. , 2008, Annual review of biochemistry.

[59]  P. V. van Diest,et al.  BRCA1 and BRCA2 germline mutation analysis in the Indonesian population , 2007, Breast Cancer Research and Treatment.

[60]  Saskia Hoffmann,et al.  CtIP-dependent DNA resection is required for DNA damage checkpoint maintenance but not initiation , 2012, The Journal of cell biology.

[61]  L. Povirk Processing of Damaged DNA Ends for Double-Strand Break Repair in Mammalian Cells , 2012, ISRN molecular biology.

[62]  Junjie Chen,et al.  DNA Damage-Induced Cell Cycle Checkpoint Control Requires CtIP, a Phosphorylation-Dependent Binding Partner of BRCA1 C-Terminal Domains , 2004, Molecular and Cellular Biology.

[63]  L. Wiesmüller,et al.  BCR-ABL stimulates mutagenic homologous DNA double-strand break repair via the DNA-end-processing factor CtIP. , 2011, Carcinogenesis.

[64]  David J. Chen,et al.  The endless tale of non-homologous end-joining , 2008, Cell Research.

[65]  M. Hung,et al.  Changes in BRCA2 expression during progression of the cell cycle. , 1997, Biochemical and biophysical research communications.

[66]  G. Iliakis,et al.  Widespread dependence of backup NHEJ on growth state: ramifications for the use of DNA-PK inhibitors. , 2011, International journal of radiation oncology, biology, physics.

[67]  K. Miyagawa Clinical relevance of the homologous recombination machinery in cancer therapy , 2008, Cancer science.

[68]  H. Kimura,et al.  Inhibitors of the proteasome suppress homologous DNA recombination in mammalian cells. , 2007, Cancer research.

[69]  J. Griffin,et al.  BCR-ABL promotes the frequency of mutagenic single-strand annealing DNA repair. , 2009, Blood.

[70]  M. Tarsounas,et al.  RAD51 paralogs: roles in DNA damage signalling, recombinational repair and tumorigenesis. , 2011, Seminars in cell & developmental biology.

[71]  S. West,et al.  Identification of Holliday junction resolvases from humans and yeast , 2008, Nature.

[72]  R. Weichselbaum,et al.  Activation of the c-Abl tyrosine kinase in the stress response to DMA-damaging agents , 1995, Nature.

[73]  S. Powell,et al.  RAD52 inactivation is synthetically lethal with deficiencies in BRCA1 and PALB2 in addition to BRCA2 through RAD51-mediated homologous recombination , 2013, Oncogene.

[74]  T. Pandita,et al.  The role of the DNA double-strand break response network in meiosis. , 2004, DNA repair.

[75]  Shridar Ganesan,et al.  BRCA1, PARP, and 53BP1: conditional synthetic lethality and synthetic viability. , 2011, Journal of molecular cell biology.

[76]  L. Povirk Biochemical mechanisms of chromosomal translocations resulting from DNA double-strand breaks. , 2006, DNA repair.

[77]  C. Le Péchoux,et al.  Radiation therapy in the management of adult soft tissue sarcomas. , 2004, Annals of oncology : official journal of the European Society for Medical Oncology.

[78]  E. Egelman,et al.  Novel pro- and anti-recombination activities of the Bloom's syndrome helicase. , 2007, Genes & development.

[79]  B. Reina-San-Martin,et al.  Parp 1 facilitates alternative NHEJ , whereas Parp 2 suppresses IgH / c-myc translocations during immunoglobulin class switch recombination , 2009 .

[80]  Lukas J A Stalpers,et al.  Inhibition of homologous recombination by hyperthermia shunts early double strand break repair to non-homologous end-joining. , 2013, DNA repair.

[81]  James B. Mitchell,et al.  In vitro and In vivo Radiation Sensitization of Human Tumor Cells by a Novel Checkpoint Kinase Inhibitor, AZD7762 , 2010, Clinical Cancer Research.

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

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

[84]  H. Rodemann,et al.  Membrane receptor signaling and control of DNA repair after exposure to ionizing radiation Membranrezeptorsignale und Kontrolle der DNA-Reparatur nach ionisierender Strahlung , 2010, Nuklearmedizin.

[85]  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.

[86]  R. Fishel,et al.  Fusion Tyrosine Kinases Induce Drug Resistance by Stimulation of Homology-Dependent Recombination Repair, Prolongation of G2/M Phase, and Protection from Apoptosis , 2002, Molecular and Cellular Biology.

[87]  Michel C. Nussenzweig,et al.  Rif1 Prevents Resection of DNA Breaks and Promotes Immunoglobulin Class Switching , 2013, Science.

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

[89]  J. Bartek,et al.  CDK targeting of NBS1 promotes DNA‐end resection, replication restart and homologous recombination , 2012, EMBO reports.

[90]  E. Yeh,et al.  Regulation of DNA repair through deSUMOylation and SUMOylation of replication protein A complex. , 2010, Molecular cell.

[91]  K. Khanna,et al.  Exo1 plays a major role in DNA end resection in humans and influences double-strand break repair and damage signaling decisions. , 2012, DNA repair.

[92]  Geoff Delaney M.B.B.S.,et al.  The role of radiotherapy in cancer treatment , 2005 .

[93]  D. Ramsden,et al.  The DNA‐dependent protein kinase: the director at the end , 2004, Immunological reviews.

[94]  Jeremy M. Stark,et al.  RI-1: a chemical inhibitor of RAD51 that disrupts homologous recombination in human cells , 2012, Nucleic acids research.

[95]  H. Nevanlinna,et al.  The DNA damage signalling kinase ATM is aberrantly reduced or lost in BRCA1/BRCA2-deficient and ER/PR/ERBB2-triple-negative breast cancer , 2008, Oncogene.

[96]  Tom Walsh,et al.  Ten genes for inherited breast cancer. , 2007, Cancer cell.

[97]  Jayanta Chaudhuri,et al.  CtIP promotes microhomology-mediated alternative end-joining during class switch recombination , 2010, Nature Structural &Molecular Biology.

[98]  Huichen Wang,et al.  Histone H1 functions as a stimulatory factor in backup pathways of NHEJ , 2008, Nucleic acids research.

[99]  Jeremy M. Stark,et al.  Alternative-NHEJ Is a Mechanistically Distinct Pathway of Mammalian Chromosome Break Repair , 2008, PLoS genetics.

[100]  M. Greaves,et al.  Origins of chromosome translocations in childhood leukaemia , 2003, Nature Reviews Cancer.

[101]  Jeremy M. Stark,et al.  53BP1 Inhibits Homologous Recombination in Brca1-Deficient Cells by Blocking Resection of DNA Breaks , 2010, Cell.

[102]  Stephanie Lamart,et al.  Proportion of second cancers attributable to radiotherapy treatment in adults: a cohort study in the US SEER cancer registries. , 2011, The Lancet. Oncology.

[103]  J. Ward,et al.  The yield of DNA double-strand breaks produced intracellularly by ionizing radiation: a review. , 1990, International journal of radiation biology.

[104]  J. Kładny,et al.  Breast cancer susceptibility genes. , 2007, Journal of B.U.ON. : official journal of the Balkan Union of Oncology.

[105]  R. Bristow,et al.  Defective DNA Strand Break Repair after DNA Damage in Prostate Cancer Cells , 2004, Cancer Research.

[106]  Stephen C. West,et al.  Molecular views of recombination proteins and their control , 2003, Nature Reviews Molecular Cell Biology.

[107]  K. Valerie,et al.  BRCA1-directed, enhanced and aberrant homologous recombination , 2012, Cell cycle.

[108]  G. Iliakis,et al.  Induction and repair of DNA double strand breaks: the increasing spectrum of non-homologous end joining pathways. , 2011, Mutation research.

[109]  Kai Rothkamm,et al.  Pathways of DNA Double-Strand Break Repair during the Mammalian Cell Cycle , 2003, Molecular and Cellular Biology.

[110]  J. Dahm-Daphi,et al.  The alternative end-joining pathway for repair of DNA double-strand breaks requires PARP1 but is not dependent upon microhomologies , 2010, Nucleic acids research.

[111]  S. Elledge,et al.  ATM–Chk2–p53 activation prevents tumorigenesis at an expense of organ homeostasis upon Brca1 deficiency , 2006, The EMBO journal.

[112]  A. Ashworth,et al.  p53 modulates homologous recombination by transcriptional regulation of the RAD51 gene , 2006, EMBO reports.

[113]  Facundo D. Batista,et al.  RIF1 Is Essential for 53BP1-Dependent Nonhomologous End Joining and Suppression of DNA Double-Strand Break Resection , 2013, Molecular cell.

[114]  Ralph Scully,et al.  Role of mammalian Mre11 in classical and alternative non-homologous end joining , 2009, Nature Structural &Molecular Biology.

[115]  Koichi Tokuuye,et al.  Role of radiotherapy in cancer treatment , 2009 .

[116]  G. Iliakis,et al.  Kinetics of DNA double-strand break repair throughout the cell cycle as assayed by pulsed field gel electrophoresis in CHO cells. , 1991, International journal of radiation biology.

[117]  Michael G. Sehorn,et al.  RECQL5/Recql5 helicase regulates homologous recombination and suppresses tumor formation via disruption of Rad51 presynaptic filaments. , 2007, Genes & development.

[118]  Adam P. Rosebrock,et al.  A cell cycle-dependent regulatory circuit composed of 53BP1-RIF1 and BRCA1-CtIP controls DNA repair pathway choice. , 2013, Molecular cell.

[119]  J. Flygare,et al.  Expression of the human RAD51 gene during the cell cycle in primary human peripheral blood lymphocytes. , 1996, Biochimica et biophysica acta.

[120]  R. Okayasu,et al.  Inhibition of homologous recombination repair in irradiated tumor cells pretreated with Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin. , 2006, Biochemical and biophysical research communications.

[121]  B. T. Bennett,et al.  Xrcc3 is recruited to DNA double strand breaks early and independent of Rad51 , 2004, Journal of cellular biochemistry.

[122]  Huichen Wang,et al.  DNA ligase III as a candidate component of backup pathways of nonhomologous end joining. , 2005, Cancer research.

[123]  T. Pandita,et al.  Phosphorylation of Exo1 modulates homologous recombination repair of DNA double-strand breaks , 2009, Nucleic acids research.

[124]  G. Maga,et al.  Human Proliferating Cell Nuclear Antigen, Poly(ADP-ribose) Polymerase-1, and p21waf1/cip1 , 2003, Journal of Biological Chemistry.

[125]  D. Adams,et al.  53BP1 loss rescues BRCA1 deficiency and is associated with triple-negative and BRCA-mutated breast cancers , 2010, Nature Structural &Molecular Biology.

[126]  Maximina H. Yun,et al.  CtIP-BRCA1 modulates the choice of DNA double-strand break repair pathway throughout the cell cycle , 2009, Nature.

[127]  J. Haber,et al.  Multiple Pathways of Recombination Induced by Double-Strand Breaks in Saccharomyces cerevisiae , 1999, Microbiology and Molecular Biology Reviews.

[128]  C. Eaves,et al.  BCR/ABL and other kinases from chronic myeloproliferative disorders stimulate single-strand annealing, an unfaithful DNA double-strand break repair. , 2008, Cancer research.

[129]  L. Bohm Inhibition of homologous recombination repair with Pentoxifylline targets G2 cells generated by radiotherapy and induces major enhancements of the toxicity of cisplatin and melphalan given after irradiation , 2006, Radiation oncology.

[130]  S. Gonzalo,et al.  The role of RPA2 phosphorylation in homologous recombination in response to replication arrest. , 2010, Carcinogenesis.

[131]  R. Kanaar,et al.  Mild hyperthermia inhibits homologous recombination, induces BRCA2 degradation, and sensitizes cancer cells to poly (ADP-ribose) polymerase-1 inhibition , 2011, Proceedings of the National Academy of Sciences.

[132]  Kara A. Bernstein,et al.  From yeast to mammals: recent advances in genetic control of homologous recombination. , 2012, DNA repair.

[133]  J. Dahm-Daphi,et al.  The epidermal growth factor receptor modulates DNA double-strand break repair by regulating non-homologous end-joining. , 2010, DNA repair.

[134]  D. Schild,et al.  Overexpression of RAD51 suppresses recombination defects: a possible mechanism to reverse genomic instability , 2009, Nucleic Acids Research.

[135]  Timothy J. Kinsella,et al.  Coordination of DNA Mismatch Repair and Base Excision Repair Processing of Chemotherapy and Radiation Damage for Targeting Resistant Cancers , 2009, Clinical Cancer Research.

[136]  S C West,et al.  Identification and purification of two distinct complexes containing the five RAD51 paralogs. , 2001, Genes & development.

[137]  W. Holloman,et al.  Compensatory role for Rad52 during recombinational repair in Ustilago maydis , 2008, Molecular microbiology.

[138]  James B. Mitchell,et al.  In Vitro and In Vivo Radiation Sensitization of Human Tumor Cells by a Novel Checkpoint Kinase Inhibitor , 2009 .

[139]  G. Iliakis,et al.  Homologous recombination as a potential target for caffeine radiosensitization in mammalian cells: reduced caffeine radiosensitization in XRCC2 and XRCC3 mutants , 2000, Oncogene.

[140]  Bruce Mickey,et al.  EGFRvIII and DNA double-strand break repair: a molecular mechanism for radioresistance in glioblastoma. , 2009, Cancer research.

[141]  T. Pandita,et al.  Rad52 inactivation is synthetically lethal with BRCA2 deficiency , 2010, Proceedings of the National Academy of Sciences.

[142]  A. Bürkle,et al.  trans-dominant inhibition of poly(ADP-ribosyl)ation sensitizes cells against gamma-irradiation and N-methyl-N'-nitro-N-nitrosoguanidine but does not limit DNA replication of a polyomavirus replicon , 1995, Molecular and cellular biology.

[143]  T. Skorski,et al.  Targeting RAD51 phosphotyrosine-315 to prevent unfaithful recombination repair in BCR-ABL1 leukemia. , 2011, Blood.

[144]  Fan Zhang,et al.  PALB2 Functionally Connects the Breast Cancer Susceptibility Proteins BRCA1 and BRCA2 , 2009, Molecular Cancer Research.

[145]  P. Sung,et al.  Mechanism of eukaryotic homologous recombination. , 2008, Annual review of biochemistry.

[146]  A. Tomkinson,et al.  Human Mre11/Human Rad50/Nbs1 and DNA Ligase IIIα/XRCC1 Protein Complexes Act Together in an Alternative Nonhomologous End Joining Pathway* , 2011, The Journal of Biological Chemistry.

[147]  Markus Löbrich,et al.  Factors determining DNA double‐strand break repair pathway choice in G2 phase , 2011, The EMBO journal.

[148]  A. Fersht,et al.  Mapping the physical and functional interactions between the tumor suppressors p53 and BRCA2 , 2010, Proceedings of the National Academy of Sciences.

[149]  S. West,et al.  CDK-dependent phosphorylation of BRCA2 as a regulatory mechanism for recombinational repair , 2005, Nature.

[150]  Stephen P. Jackson,et al.  Human CtIP Mediates Cell Cycle Control of DNA End Resection and Double Strand Break Repair*S⃞ , 2009, Journal of Biological Chemistry.

[151]  S C West,et al.  BRCA2: a universal recombinase regulator , 2007, Oncogene.

[152]  S. Adimoolam,et al.  HDAC inhibitor PCI-24781 decreases RAD51 expression and inhibits homologous recombination , 2007, Proceedings of the National Academy of Sciences.

[153]  A. Jemal,et al.  Cancer treatment and survivorship statistics, 2012 , 2012, CA: a cancer journal for clinicians.

[154]  P. Dhar,et al.  Rad52 partially substitutes for the Rad51 paralog XRCC3 in maintaining chromosomal integrity in vertebrate cells , 2001, The EMBO journal.

[155]  H. Kurumizaka,et al.  c-ABL tyrosine kinase stabilizes RAD51 chromatin association. , 2009, Biochemical and biophysical research communications.

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

[157]  G. Iliakis,et al.  Backup Pathways of Nonhomologous End Joining May Have a Dominant Role in the Formation of Chromosome Aberrations , 2007 .

[158]  W. Zhong,et al.  High-level expression of Rad51 is an independent prognostic marker of survival in non-small-cell lung cancer patients , 2005, British Journal of Cancer.

[159]  K. Shirahige,et al.  Spo11-Accessory Proteins Link Double-Strand Break Sites to the Chromosome Axis in Early Meiotic Recombination , 2011, Cell.

[160]  D. Ramsden,et al.  Specificity of the dRP/AP Lyase of Ku Promotes Nonhomologous End Joining (NHEJ) Fidelity at Damaged Ends* , 2012, The Journal of Biological Chemistry.

[161]  R. Bristow,et al.  Targeting homologous recombination using imatinib results in enhanced tumor cell chemosensitivity and radiosensitivity , 2009, Molecular Cancer Therapeutics.

[162]  K. Weber,et al.  Overexpression of the DNA-binding domain of poly(ADP-ribose) polymerase inhibits rejoining of ionizing radiation-induced DNA double-strand breaks , 2001, International journal of radiation biology.

[163]  Cheng Chen Regulation of DNA Double Strand Break Response , 2014 .

[164]  C. Richardson RAD51, genomic stability, and tumorigenesis. , 2005, Cancer letters.

[165]  G. Speit,et al.  Chromosomal mutagen sensitivity associated with mutations in BRCA genes , 2004, Cytogenetic and Genome Research.

[166]  R. Fishel,et al.  BCR/ABL regulates mammalian RecA homologs, resulting in drug resistance. , 2001, Molecular cell.

[167]  Edward H Egelman,et al.  Stabilization of RAD51 nucleoprotein filaments by the C-terminal region of BRCA2 , 2007, Nature Structural &Molecular Biology.

[168]  A. Yasui,et al.  Spatial and Temporal Cellular Responses to Single-Strand Breaks in Human Cells , 2003, Molecular and Cellular Biology.

[169]  M. Lieber,et al.  The mechanism of double-strand DNA break repair by the nonhomologous DNA end-joining pathway. , 2010, Annual review of biochemistry.

[170]  Rochelle L. Garcia,et al.  Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing , 2011, Proceedings of the National Academy of Sciences.

[171]  M. Fukushima,et al.  Gimeracil sensitizes cells to radiation via inhibition of homologous recombination. , 2010, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[172]  B. A. Ballif,et al.  ATM and ATR Substrate Analysis Reveals Extensive Protein Networks Responsive to DNA Damage , 2007, Science.

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

[174]  A. Tomkinson,et al.  Up-regulation of WRN and DNA ligase IIIalpha in chronic myeloid leukemia: consequences for the repair of DNA double-strand breaks. , 2008, Blood.

[175]  W. Heyer,et al.  RAD54 controls access to the invading 3′-OH end after RAD51-mediated DNA strand invasion in homologous recombination in Saccharomyces cerevisiae , 2008, Nucleic acids research.

[176]  Y. Shiloh,et al.  Functional link of BRCA1 and ataxia telangiectasia gene product in DNA damage response , 2000, Nature.

[177]  Hong Wang,et al.  Erlotinib attenuates homologous recombinational repair of chromosomal breaks in human breast cancer cells. , 2008, Cancer research.

[178]  M. Fukushima,et al.  A nucleoside anticancer drug, 1-(3-C-ethynyl-β-D-ribo-pentofuranosyl)cytosine (TAS106), sensitizes cells to radiation by suppressing BRCA2 expression , 2011, Molecular Cancer.

[179]  M. Leversha,et al.  Intra-nuclear trafficking of the BLM helicase to DNA damage-induced foci is regulated by SUMO modification. , 2005, Human molecular genetics.

[180]  Melanie Keppler,et al.  The SUMO modification pathway is involved in the BRCA1 response to genotoxic stress , 2009, Nature.

[181]  S. Cocklin,et al.  Inhibition of homologous recombination in human cells by targeting RAD51 recombinase. , 2012, Journal of medicinal chemistry.

[182]  S. West,et al.  Telomere Maintenance Requires the RAD51D Recombination/Repair Protein , 2004, Cell.

[183]  R. Weichselbaum,et al.  Pilot study examining tumor expression of RAD51 and clinical outcomes in human head cancers. , 2006, International journal of oncology.

[184]  Lei Zhang,et al.  DNA Ligase III Promotes Alternative Nonhomologous End-Joining during Chromosomal Translocation Formation , 2011, PLoS genetics.

[185]  T Hyslop,et al.  DNA-dependent protein kinase stimulates an independently active, nonhomologous, end-joining apparatus. , 2000, Cancer research.

[186]  T. Skorski,et al.  BCR/ABL regulates response to DNA damage: the role in resistance to genotoxic treatment and in genomic instability , 2002, Oncogene.

[187]  M. Leslie,et al.  How to live without BRCA1 , 2013, The Journal of Cell Biology.

[188]  Dihua Yu,et al.  Rad51 overexpression contributes to chemoresistance in human soft tissue sarcoma cells: a role for p53/activator protein 2 transcriptional regulation , 2007, Molecular Cancer Therapeutics.

[189]  Stefano Ferrari,et al.  DNA end resection by CtIP and exonuclease 1 prevents genomic instability , 2010, EMBO reports.

[190]  A. Knudson,et al.  Endogenous DNA double-strand breaks: Production, fidelity of repair, and induction of cancer , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[191]  J. Nickoloff,et al.  Regulation of DNA double-strand break repair pathway choice , 2008, Cell Research.

[192]  H. Arakawa,et al.  DNA Ligases I and III Cooperate in Alternative Non-Homologous End-Joining in Vertebrates , 2013, PloS one.

[193]  M. Lederman Advances in radiotherapy. , 1970, The Practitioner.

[194]  George Iliakis,et al.  Backup pathways of NHEJ in cells of higher eukaryotes: cell cycle dependence. , 2009, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[195]  C. Mayer,et al.  Nuclear EGFR as Novel Therapeutic Target , 2009, Strahlentherapie und Onkologie.

[196]  J. Dahm-Daphi,et al.  In tumor cells regulation of DNA double strand break repair through EGF receptor involves both NHEJ and HR and is independent of p53 and K-Ras status. , 2011, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[197]  Amy J. Hawkins,et al.  Pro-survival AKT and ERK signaling from EGFR and mutant EGFRvIII enhances DNA double-strand break repair in human glioma cells , 2009, Cancer biology & therapy.

[198]  D. Schatz,et al.  V(D)J recombination: mechanisms of initiation. , 2011, Annual review of genetics.

[199]  Steven P Gygi,et al.  Abraxas and RAP80 Form a BRCA1 Protein Complex Required for the DNA Damage Response , 2007, Science.

[200]  G. Sauter,et al.  RAD51 overexpression is a negative prognostic marker for colorectal adenocarcinoma , 2013, International journal of cancer.

[201]  R. Bristow,et al.  Imatinib radiosensitizes bladder cancer by targeting homologous recombination. , 2013, Cancer research.

[202]  J. Haber,et al.  Genetic requirements for the single-strand annealing pathway of double-strand break repair in Saccharomyces cerevisiae. , 1996, Genetics.

[203]  S. Smerdon,et al.  Plk1 and CK2 Act in Concert to Regulate Rad51 during DNA Double Strand Break Repair , 2012, Molecular cell.

[204]  C. Liao,et al.  RAD51C facilitates checkpoint signaling by promoting CHK2 phosphorylation , 2009, The Journal of cell biology.

[205]  Y. Zou,et al.  DNA-PK, ATM and ATR collaboratively regulate p53-RPA interaction to facilitate homologous recombination DNA repair , 2012, Oncogene.

[206]  S. Vispé,et al.  Overexpression of Rad51 protein stimulates homologous recombination and increases resistance of mammalian cells to ionizing radiation. , 1998, Nucleic acids research.

[207]  Junjie Chen,et al.  BRCA1 ubiquitinates its phosphorylation-dependent binding partner CtIP. , 2006, Genes & development.

[208]  D. Ward,et al.  Nuclear foci of mammalian Rad51 recombination protein in somatic cells after DNA damage and its localization in synaptonemal complexes. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[209]  D. Aebersold,et al.  MET inhibition in tumor cells by PHA665752 impairs homologous recombination repair of DNA double strand breaks , 2012, International journal of cancer.

[210]  P. Calsou,et al.  Involvement of Poly(ADP-ribose) Polymerase-1 and XRCC1/DNA Ligase III in an Alternative Route for DNA Double-strand Breaks Rejoining* , 2004, Journal of Biological Chemistry.