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  • Original Paper
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DNA damage-induced cell cycle checkpoints and DNA strand break repair in development and tumorigenesis

Abstract

Several newly identified tumor suppressor genes including ATM, NBS1, BRCA1 and BRCA2 are involved in DNA double-strand break repair (DSBR) and DNA damage-induced checkpoint activation. Many of the gene products involved in checkpoint control and DSBR have been studied in great detail in yeast. In addition to evolutionarily conserved proteins such as Chk1 and Chk2, studies in mammalian cells have identified novel proteins such as p53 in executing checkpoint control. DSBR proteins including Mre11, Rad50, Rad51, Rad54, and Ku are present in yeast and in mammals. Many of the tumor suppressor gene products interact with these repair proteins as well as checkpoint regulators, thus providing a biochemical explanation for the pleiotropic phenotypes of mutant cells. This review focuses on the proteins mediating G1/S, S, and G2/M checkpoint control in mammalian cells. In addition, mammalian DSBR proteins and their activities are discussed. An intricate network among DNA damage signal transducers, cell cycle regulators and the DSBR pathways is illustrated. Mouse knockout models for genes involved in these processes have provided valuable insights into their function, establishing genomic instability as a major contributing factor in tumorigenesis.

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Abbreviations

ATM:

ataxia-telangiectasia mutated

BRCT:

BRCA1 carboxyl terminus

DSB:

double-strand break

DSBR:

double-strand break repair

FHA:

forkhead-associated

HR:

homologous recombination

IR:

ionizing radiation

IRIF:

ionizing radiation-induced immunofluorescent foci

MMS:

methyl-methane-sulfonate

NBS:

Nijmegen breakage syndrome

NHEJ:

non-homologous end joining

RDS:

radiation-resistant DNA synthesis

SCID:

severe combined immune deficient

SDDC:

S phase DNA damage checkpoint

TCR:

T cell receptor

XRCC:

X-ray repair cross complementation

Atm:

Mouse homologs are represented in lower case

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Acknowledgements

We thank Dr W-H Lee and members of participating laboratories of the program project for enlightening discussions; and Drs E Brown and P Hasty for sharing unpublished results. E Lee is supported by a grant from Texas Advanced Research/Advanced Technology Program (ATP3659-034), and National Institutes of Health Grant (1R01NS378381). GK Dasika is a recipient of Susan G Komen postdoctoral fellowship. S Zhao is supported by DOD training grant (DAMD17–99–1–9402).

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Dasika, G., Lin, SC., Zhao, S. et al. DNA damage-induced cell cycle checkpoints and DNA strand break repair in development and tumorigenesis. Oncogene 18, 7883–7899 (1999). https://doi.org/10.1038/sj.onc.1203283

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