DNA damage tumor suppressor genes and genomic instability

Curr Opin Genet Dev. 2004 Feb;14(1):11-6. doi: 10.1016/j.gde.2003.12.003.


Disruption of the mechanisms that regulate cell-cycle checkpoints, DNA repair, and apoptosis results in genomic instability and the development of cancer in multicellular organisms. The protein kinases ATM and ATR, as well as their downstream substrates Chk1 and Chk2, are central players in checkpoint activation in response to DNA damage. Histone H2AX, ATRIP, as well as the BRCT-motif-containing molecules 53BP1, MDC1, and BRCA1 function as molecular adapters or mediators in the recruitment of ATM or ATR and their targets to sites of DNA damage. The increased chromosomal instability and tumor susceptibility apparent in mutant mice deficient in both p53 and either histone H2AX or proteins that contribute to the nonhomologous end-joining mechanism of DNA repair indicate that DNA damage checkpoints play a pivotal role in tumor suppression.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Apoptosis / genetics
  • Apoptosis / physiology
  • DNA Damage / genetics*
  • DNA Damage / physiology
  • DNA Repair / genetics*
  • Genes, Tumor Suppressor / physiology*
  • Genes, cdc / physiology*
  • Genomic Instability*