Endogenous DNA double-strand breaks: Production, fidelity of repair, and induction of cancer

This article extends our previous quantitative analysis of the relationship between the dynamics of the primary structure of DNA and mutagenesis associated with single-strand lesions to an analysis of the production and processing of endogenous double-strand breaks (EDSBs) and to their implications for oncogenesis. We estimate that in normal human cells ≈1% of single-strand lesions are converted to ≈50 EDSBs per cell per cell cycle. This number is similar to that for EDSBs produced by 1.5–2.0 Gy of sparsely ionizing radiation. Although EDSBs are usually repaired with high fidelity, errors in their repair contribute significantly to the rate of cancer in humans. The doubling dose for induced DSBs is similar to doubling doses for mutation and for the induction of carcinomas by ionizing radiation. We conclude that rates of production of EDSBs and of ensuing spontaneous mitotic recombination events can account for a substantial fraction of the earliest oncogenic events in human carcinomas.

[1]  J. Haber,et al.  Lack of chromosome territoriality in yeast: promiscuous rejoining of broken chromosome ends. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[2]  George Lliakis,et al.  The role of DNA double strand breaks in lonizing radiation‐induced killing of eukaryotic cells , 1991 .

[3]  A. Pastink,et al.  DNA Double-Strand Break Repair by Homologous Recombination , 2002, Biological chemistry.

[4]  R. Rothstein,et al.  Rad52 forms DNA repair and recombination centers during S phase , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[5]  D. Baltimore,et al.  Radiation-induced Assembly of Rad51 and Rad52 Recombination Complex Requires ATM and c-Abl* , 1999, The Journal of Biological Chemistry.

[6]  D. Ramsden,et al.  V(D)J recombination: links to transposition and double-strand break repair. , 1999, Cold Spring Harbor symposia on quantitative biology.

[7]  M. Bibikova,et al.  Mre11 protein complex prevents double-strand break accumulation during chromosomal DNA replication. , 2001, Molecular cell.

[8]  E. Rogakou,et al.  Megabase Chromatin Domains Involved in DNA Double-Strand Breaks in Vivo , 1999, The Journal of cell biology.

[9]  A. Bradley,et al.  Cancer predisposition caused by elevated mitotic recombination in Bloom mice , 2000, Nature Genetics.

[10]  Bo Stenerlöw,et al.  Measurement of Prompt DNA Double-Strand Breaks in Mammalian Cells without Including Heat-Labile Sites: Results for Cells Deficient in Nonhomologous End Joining , 2002, Radiation research.

[11]  T. Pandita,et al.  Regulation of DNA-dependent Protein Kinase Activity by Ionizing Radiation-activated Abl Kinase Is an ATM-dependent Process* , 2000, The Journal of Biological Chemistry.

[12]  B. Ames,et al.  Endogenous DNA damage as related to cancer and aging. , 1989, Mutation research.

[13]  O. Sieber,et al.  Analysis of chromosomal instability in human colorectal adenomas with two mutational hits at APC , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[14]  R. Bos,et al.  Mutagens in urine of non-smoking and smoking workers in an aircraft tyre retreading plant. Skin exposure as a causal factor? , 1989, Mutation research.

[15]  A. Knudson,et al.  Inverse radiation dose-rate effects on somatic and germ-line mutations and DNA damage rates. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[16]  K. Kinzler,et al.  Mechanisms underlying losses of heterozygosity in human colorectal cancers , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[17]  B. Hann,et al.  Purification and DNA binding properties of the ataxia-telangiectasia gene product ATM. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[18]  Y. Shiloh,et al.  Nuclear retention of ATM at sites of DNA double strand breaks. , 2001, The Journal of biological chemistry.

[19]  L. Samson,et al.  A Chemical and Genetic Approach Together Define the Biological Consequences of 3-Methyladenine Lesions in the Mammalian Genome* , 1998, The Journal of Biological Chemistry.

[20]  R. Daniel,et al.  A role for DNA-PK in retroviral DNA integration. , 1999, Science.

[21]  Jeremy M. Stark,et al.  Double-strand breaks and tumorigenesis. , 2001, Trends in cell biology.

[22]  J. Tymowska.  A comparative study of the karyotypes of eight Xenopus species and subspecies possessing a 36-chromosome complement. , 1977, Cytogenetics and cell genetics.

[23]  M. Jasin,et al.  Double-strand-break-induced homologous recombination in mammalian cells. , 2001, Biochemical Society transactions.

[24]  P. Jeggo,et al.  Constitutive Association of BRCA1 and c-Abl and Its ATM-Dependent Disruption after Irradiation , 2002, Molecular and Cellular Biology.

[25]  W. Bonner,et al.  Low-dose radiation: Thresholds, bystander effects, and adaptive responses , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[26]  W. Bigbee,et al.  Evidence for increased in vivo mutation and somatic recombination in Bloom's syndrome. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[27]  E. Rogakou,et al.  DNA Double-stranded Breaks Induce Histone H2AX Phosphorylation on Serine 139* , 1998, The Journal of Biological Chemistry.

[28]  Kai Rothkamm,et al.  Evidence for a lack of DNA double-strand break repair in human cells exposed to very low x-ray doses , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[29]  D A Pierce,et al.  Radiation-Related Cancer Risks at Low Doses among Atomic Bomb Survivors , 2000, Radiation research.

[30]  J. Tischfield,et al.  Somatic recombination redux , 2003, Nature Genetics.

[31]  P. Jeggo,et al.  Radiation-induced genomic rearrangements formed by nonhomologous end-joining of DNA double-strand breaks. , 2001, Cancer research.

[32]  T. Dryja,et al.  Mitotic recombination map of 13cen-13q14 derived from an investigation of loss of heterozygosity in retinoblastomas. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[33]  P. Jeggo,et al.  DNA breakage and repair. , 1998, Advances in genetics.

[34]  B. Ames,et al.  Oxidative damage to DNA: relation to species metabolic rate and life span. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[35]  J. Hoeijmakers,et al.  Molecular mechanisms of DNA double strand break repair. , 1998, Trends in cell biology.

[36]  B. Gallie,et al.  Mechanisms of loss of heterozygosity in retinoblastoma. , 1992, Cytogenetics and cell genetics.

[37]  S. Elledge,et al.  BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures. , 2000, Genes & development.

[38]  S. Inoue,et al.  Functional interaction between DNA-PK and c-Abl in response to DNA damage , 1997, Nature.

[39]  V. Yamazaki,et al.  A critical role for histone H2AX in recruitment of repair factors to nuclear foci after DNA damage , 2000, Current Biology.

[40]  M. Cox.  Historical overview: Searching for replication help in all of the rec places , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[41]  L. Loeb,et al.  Mutagenesis by apurinic/apyrimidinic sites. , 1986, Annual review of genetics.

[42]  Christine Richardson,et al.  Frequent chromosomal translocations induced by DNA double-strand breaks , 2000, Nature.

[43]  S. West,et al.  Branch Migration and Holliday Junction Resolution Catalyzed by Activities from Mammalian Cells , 2001, Cell.

[44]  T. Lindahl.  Instability and decay of the primary structure of DNA , 1993, Nature.

[45]  Michael M. Murphy,et al.  ATM Phosphorylates Histone H2AX in Response to DNA Double-strand Breaks* , 2001, The Journal of Biological Chemistry.

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

[47]  J. Essigmann,et al.  Possible role for thymine glycol in the selective inhibition of DNA synthesis on oxidized DNA templates. , 1985, Cancer research.

[48]  Jean Y. J. Wang.  Regulation of cell death by the Abl tyrosine kinase , 2000, Oncogene.

[49]  M. Maccabee,et al.  Pyrimidine ring fragmentation products. Effects of lesion structure and sequence context on mutagenesis. , 1994, Journal of molecular biology.

[50]  A. Ashworth,et al.  Mutation in Brca2 stimulates error‐prone homology‐directed repair of DNA double‐strand breaks occurring between repeated sequences , 2001, The EMBO journal.

[51]  S. Wallace,et al.  Abortive base-excision repair of radiation-induced clustered DNA lesions in Escherichia coli , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[52]  Junjie Chen,et al.  Mediator of DNA Damage Checkpoint Protein 1 Regulates BRCA1 Localization and Phosphorylation in DNA Damage Checkpoint Control* , 2003, The Journal of Biological Chemistry.

[53]  M. Kastan,et al.  DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation , 2003, Nature.

[54]  K. Haigis,et al.  A Robertsonian translocation suppresses a somatic recombination pathway to loss of heterozygosity , 2003, Nature Genetics.

[55]  Yonghong Xiao,et al.  Association of BRCA1 with Rad51 in Mitotic and Meiotic Cells , 1997, Cell.

[56]  B. Jerkovič,et al.  Replication inhibition and miscoding properties of DNA templates containing a site-specific cis-thymine glycol or urea residue. , 1998, Chemical research in toxicology.

[57]  L. Grossman,et al.  Mechanisms of DNA Damage and Repair , 1986, Basic Life Sciences.

[58]  D. Preston,et al.  Cancer incidence in atomic bomb survivors. Part II: Solid tumors, 1958-1987. , 1994, Radiation research.

[59]  J. Haber.  DNA recombination: the replication connection. , 1999, Trends in biochemical sciences.

[60]  G. Eichele,et al.  Embryonic lethality and radiation hypersensitivity mediated by Rad51 in mice lacking Brca2 , 1997, Nature.

[61]  David J. Chen,et al.  DNA-dependent protein kinase suppresses double-strand break-induced and spontaneous homologous recombination , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[62]  A. Kuzminov.  DNA replication meets genetic exchange: Chromosomal damage and its repair by homologous recombination , 2001, Proceedings of the National Academy of Sciences of the United States of America.