To ensure the high-fidelity transmission of genetic information, cells have evolved mechanisms to monitor genome integrity. Cells respond to DNA damage by activating a complex DNA-damage-response pathway that includes cell-cycle arrest, the transcriptional and post-transcriptional activation of a subset of genes including those associated with DNA repair, and, under some circumstances, the triggering of programmed cell death. An inability to respond properly to, or to repair, DNA damage leads to genetic instability, which in turn may enhance the rate of cancer development. Indeed, it is becoming increasingly clear that deficiencies in DNA-damage signaling and repair pathways are fundamental to the etiology of most, if not all, human cancers. Here we describe recent progress in our understanding of how cells detect and signal the presence and repair of one particularly important form of DNA damage induced by ionizing radiation—the DNA double-strand break (DSB). Moreover, we discuss how tumor suppressor proteins such as p53, ATM, Brca1 and Brca2 have been linked to such pathways, and how accumulating evidence is connecting deficiencies in cellular responses to DNA DSBs with tumorigenesis.
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Lee, S.E. et al. Saccharomyces Ku70, Mre11/Rad50, and RPA proteins regulates adaptation to G2/M arrest after DNA damage. Cell 94, 399–409 (1998).
Rich, T., Allen, R.L & Wyllie, A.H. Defying death after DNA damage. Nature 407, 777–783 (2000).
Nikiforova, M.N. et al. Proximity of chromosomal loci that participate in radiation-induced rearrangements in human cells. Science 290, 138–141 (2000)
Vamvakas, S., Vock, E.H. & Lutz, W.K. On the role of DNA double-strand breaks in toxicity and carcinogenesis. Crit. Rev. Toxicol. 27, 155–174 (1997).
Richardson, C. & Jasin, M. Frequent chromosomal translocations induced by DNA double-strand breaks. Nature 405, 697–700 (2000).
Haber, J.E. Partners and pathways repairing a double-strand break. Trends Genet. 16, 259–264 (2000).
Karran, P. DNA double strand break repair in mammalian cells. Curr. Opin. Genet. Dev. 10, 144–150 (2000).
Johnson, R.D. & Jasin, M. Sister chromatid gene conversion is a prominent double-strand break repair pathway in mammalian cells. EMBO J. 19, 3398–3407 (2000).
Tsuzuki, T. et al. Targeted disruption of the Rad51 gene leads to lethality in embryonic mice. Proc. Natl. Acad. Sci. USA 93, 6236–6240 (1996).
Tashiro, S., Walter, J., Shinohara, A., Kamada, N. & Cremer, T. Rad51 accumulation at sites of DNA damage and in post replicative chromatin. J. Cell Biol. 150, 283–291 (2000).
Liu, N. et al. XRCC2 and XRCC3, new human Rad51-family members, promote chromosome stability and protect against DNA cross-links and other damages. Mol. Cell 1, 783–793 (1998).
Essers, J. et al. Disruption of mouse RAD54 reduces ionizing radiation resistance and homologous recombination. Cell 89, 195–204 (1997).
Hiramoto, T. et al. Mutations of a novel human RAD54 homologue, RAD54B, in primary cancer. Oncogene 18, 3422–3426 (1999).
Matsuda, M. et al. Mutations in the Rad54 recombination gene in primary cancer. Oncogene 18, 3427–3430 (1999).
Rijkers, T. et al. Targeted inactivation of mouse RAD52 reduces homologous recombination but not resistance to ionizing radiation. Mol. Cell. Biol. 18, 6423–6429 (1998).
Haber, J.E. DNA repair. Gatekeepers of recombination. Nature 398, 665–667 (1999).
Welcsh, P.L., Owens, K.N. & King, M.C. Insights into the functions of BRCA1 and BRCA2. Trends Genet. 16, 69–74 (2000).
Hakem, R., de la Pompa, J.L., Elia, A., Potter, J. & Mak, T.W. Partial rescue of Brca1 (5-6) early embryonic lethality by p53 or p21 null mutation. Nature Genet. 16, 298–302 (1997).
Sharan, S.K. et al. Embryonic lethality and radiation hypersensitivity mediated by Rad51 in mice lacking Brca2. Nature 386, 804–810 (1997).
Bochar, D.A. et al. BRCA1 is associated with a human SWI/SNF-related complex: linking chromatin remodeling to breast cancer. Cell 102, 257–265 (2000).
Zhong, Q. et al. Association of BRCA1 with the hRad50-hMre11-p95 complex and the DNA damage response. Science 285, 747–750 (1999).
Phillips, K.A. et al. Frequency of p53 mutations in breast carcinomas from Ashkenazi Jewish carriers of BRCA1 mutations. J. Natl. Cancer Inst. 91, 469–473 (1999).
Xu, X. et al. Conditional mutation of Brca1 in mammary epithelial cells results in blunted ductal morphogenesis and tumour formation. Nature Genet. 22, 37–43 (1999).
Xu, X. et al. Centrosome amplification and a defective G2-M cell cycle checkpoint induce genetic instability in BRCA1 exon 11 isoform-deficient cells. Mol. Cell 3, 389–395 (1999).
Lee, H. et al. Mitotic checkpoint inactivation fosters transformation in cells lacking the breast cancer susceptibility gene, Brca2. Mol. Cell 4, 1–10 (1999).
Khanna, K.K. ATM gene and cancer risk: a continuing debate. J. Natl. Cancer Inst. 92, 795–802 (2000).
Petiniot, L.K. et al. Recombinase-activating gene (RAG) 2-mediated V(D)J recombination is not essential for tumorigenesis in Atm-deficient mice. Proc. Natl. Acad. Sci. USA 97, 6664–6669 (2000).
Bishop, A.J., Barlow, C., Wynshaw-Boris, A.J. & Schiestl, R.H. Atm deficiency causes an increased frequency of intrachromosomal homologous recombination in mice. Cancer Res. 60, 395–399 (2000).
Morrison, C. et al. The controlling role of ATM in homologous recombinational repair of DNA damage. EMBO J. 19, 463–471 (2000).
Barlow, C. et al. Atm deficiency results in severe meiotic disruption as early as leptonema of prophase I. Development 125, 4007–4017 (1998).
Rotman, G. & Shiloh, Y. ATM: a mediator of multiple responses to genotoxic stress. Oncogene 18, 6135–6144 (1999).
Saintigny, Y., Rouillard, D., Chaput, B., Soussi, T. & Lopez, B.S. Mutant p53 proteins stimulate spontaneous and radiation-induced intrachromosomal homologous recombination independently of the alteration of the transactivation activity and of the G1 checkpoint. Oncogene 18, 3553–3563 (1999).
Smilenov, L.B., Dhar, S. & Pandita, T.K. Altered telomere nuclear matrix interactions and nucleosomal periodicity in ataxia telangiectasia cells before and after ionizing radiation treatment. Mol. Cell. Biol. 19, 6963–6971 (1999).
Ikura, T. et al. Involvement of the TIP60 histone acetylase complex in DNA repair and apoptosis. Cell 102, 463–473 (2000).
Karow, J.K., Wu, L. & Hickson, I.D. RecQ family helicases: roles in cancer and aging. Curr. Opin. Genet. Dev. 10, 32–38 (2000).
Smith, G.C. & Jackson, S.P. The DNA-dependent protein kinase. Genes Dev. 13, 916–934 (1999).
Petrini, J.H. The Mre11 complex and ATM: collaborating to navigate S phase. Curr. Opin. Cell. Biol. 12, 293–296 (2000).
Carney, J.P. et al. The hMre11/hRad50 protein complex and Nijmegen breakage syndrome: linkage of double-strand break repair to the cellular DNA damage response. Cell 93, 477–486 (1998).
Varon, R. et al. Nibrin, a novel DNA double-strand break repair protein, is mutated in Nijmegen breakage syndrome. Cell 93, 467–476 (1998).
Stewart, G.S. et al. The DNA double-strand break repair gene hMRE11 is mutated in individuals with an ataxia-telangiectasia-like disorder. Cell 99, 577–587 1999).
Lim, D.S. et al. ATM phosphorylates p95/nbs1 in an S-phase checkpoint pathway. Nature 404, 613–617 (2000).
Gatei, M. et al. ATM-dependent phosphorylation of nibrin in response to radiation exposure. Nature Genet. 25, 115–119 (2000).
Zhao, S. et al. Functional link between ataxia-telangiectasia and Nijmegen breakage syndrome gene products. Nature 405, 473–477 (2000).
Wu, X. et al. ATM phosphorylation of Nijmegen breakage syndrome protein is required in a DNA damage response. Nature 405, 477–482 (2000).
Riballo, E. Identification of a defect in DNA ligase IV in a radiosensitive leukaemia patient. Curr. Biol. 9, 699–702 (1999).
Gao, Y. et al. Interplay of p53 and DNA-repair protein XRCC4 in tumorigenesis, genomic stability and development. Nature 404, 897–900 (2000).
Frank, K.M. et al. DNA ligase IV deficiency in mice leads to defective neurogenesis and embryonic lethality via the p53 pathway. Mol. Cell 5, 993–1002 (2000).
Gu, Y. et al. Defective embryonic neurogenesis in Ku-deficient but not DNA-dependent protein kinase catalytic subunit-deficient mice. Proc. Natl. Acad. Sci. USA 97, 2668–2673 (2000).
Lee, Y., Barnes, D.E., Lindahl, T. & McKinnon, P.J. Defective neurogenesis resulting from DNA ligase IV deficiency requires Atm. Genes Dev. 14, 2576–2580 (2000).
Oka, A. & Takashima, S. Expression of the ataxia-telangiectasia gene (ATM) product in human cerebellar neurons during development. Neurosci. Lett. 252, 195–198 (1998).
Difilippantonio, M.J. et al. DNA repair protein Ku80 suppresses chromosomal aberrations and malignant transformation. Nature 404, 510–514 (2000).
Vanasse, G.J. et al. Genetic pathway to recurrent chromosome translocations in murine lymphoma involves V(D)J recombinase. J. Clin. Invest. 103, 1669–1675 (1999).
Nacht, M. et al. Mutations in the p53 and SCID genes cooperate in tumorigenesis. Genes Dev. 10, 2055–2066 (1996).
Jeggo, P.A., Carr, A.M. & Lehmann, A.R. Splitting the ATM: distinct repair and checkpoint defects in ataxia-telangiectasia. Trends Genet. 14, 312–316 (1998).
Tanaka, H. et al. A ribonucleotide reductase gene involved in a p53-dependent cell-cycle checkpoint for DNA damage. Nature 404, 42–49 (2000).
Bashkirov, V.I., King, J.S., Bashkirova, E.V., Schmuckli-Maurer, J. & Heyer, W.D. DNA repair protein Rad55 is a terminal substrate of the DNA damage checkpoints. Mol. Cell. Biol. 20, 4393–4404 (2000).
Kim, S.T., Lim, D.S., Canman, C.E. & Kastan, M.B. Substrate specificities and identification of putative substrates of ATM kinase family members. J. Biol. Chem. 274, 37538–37543 (1999).
Cliby, W.A. et al. Overexpression of a kinase-inactive ATR protein causes sensitivity to DNA-damaging agents and defects in cell cycle checkpoints. EMBO J. 2, 159–169 (1998).
Tibbetts, R.S. et al. A role for ATR in the DNA damage-induced phosphorylation of p53. Genes Dev. 13, 152–157 (1999).
Brown, E.J. & Baltimore, D. ATR disruption leads to chromosomal fragmentation and early embryonic lethality. Genes Dev. 14, 397–402 (2000).
de Klein, A. et al. Targeted disruption of the cell-cycle checkpoint gene ATR leads to early embryonic lethality in mice. Curr. Biol. 10, 479–482 (2000).
Bork, P. et al. A superfamily of conserved domains in DNA damage-responsive cell cycle checkpoint proteins. FASEB J. 11, 68–76 (1997).
Wang, Y. et al. BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures. Genes Dev. 14, 927–939 (2000).
Harkin, D.P. et al. Induction of GADD45 and JNK/SAPK-dependent apoptosis following inducible expression of BRCA1. Cell 97, 575–586 (1999).
MacLachlan, T.K. et al. BRCA1 effects on the cell cycle and the DNA damage response are linked to altered gene expression. J. Biol. Chem. 275, 2777–2785 (2000).
Zhou, B.-B. et al. Caffeine abolishes the mammalian G2/M DNA damage checkpoint by inhibiting ataxia-telangiectasia-mutated kinase activity. J. Biol. Chem. 275, 10342–10348 (2000).
Matsuoka, S. et al. Ataxia telangiectasia-mutated phosphorylates Chk2 in vivo and in vitro. Proc. Natl. Acad. Sci. USA 97, 10389–10394 (2000).
Sanchez, Y. et al. Conservation of the Chk1 checkpoint pathway in mammals: linkage of DNA damage to Cdk regulation through Cdc25. Science 277, 1497–501 (1997).
Takai, H. et al. Aberrant cell cycle checkpoint function and early embryonic death in Chk1−/− mice. Genes Dev. 12, 1439–1447 (2000).
Liu, Q. et al. Chk1 is an essential kinase that is regulated by ATR and required for the G2/M DNA damage checkpoint. Genes Dev. 14, 1448–1459 (2000).
O'Connell, M.J., Walworth, N.C. & Carr, A.M. The G2-phase DNA-damage checkpoint. Trends Cell Biol. 10, 296–303 (2000).
Passalaris, T.M., Benanti, J.A., Gewin, L., Kiyono, T. & Galloway, D.A. The G(2) checkpoint is maintained by redundant pathways. Mol. Cell. Biol. 19, 5872–5881 (1999).
Caspari, T. How to activate p53. Curr. Biol. 10, R315–317 (2000).
Hirao, A. et al. DNA damage-induced activation of p53 by the checkpoint kinase Chk2. Science 287, 1824–1827 (2000).
Bell, D. et al. Heterozygous germ line hCHK2 mutations in Li-Fraumeni syndrome. Science 286, 2528–2531 (1999).
Lee, J.S., Collins, K.M., Brown, A.L., Lee, C.H. & Chung, J.H. hCds1-mediated phosphorylation of BRCA1 regulates the DNA damage response. Nature 404, 201–204 (2000).
We thank members of the Khanna and Jackson Laboratories for discussions, and J. Bradbury for editorial and scientific advice. We apologize to colleagues whose work we could not cite due to space restrictions. The Khanna laboratory is funded by grants from the National Health and Medical Research Council (Australia), the Queensland Cancer Fund (Australia) and the Susan G. Komen Breast Cancer Foundation (USA). The Jackson Laboratory is funded by grants from the Cancer Research Campaign, the Association for International Cancer Research and the A-T Medical Research Trust.
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Khanna, K., Jackson, S. DNA double-strand breaks: signaling, repair and the cancer connection. Nat Genet 27, 247–254 (2001). https://doi.org/10.1038/85798
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