Functional interaction of H2AX, NBS1, and p53 in ATM-dependent DNA damage responses and tumor suppression

Jian Kang, David Ferguson, Hoseok Song, Craig Bassing, Mark Eckersdorff, Frederick W. Alt, Yang Xu

Research output: Contribution to journalArticle

87 Citations (Scopus)

Abstract

Ataxia-telangiectasia (A-T) mutated (ATM) kinase signals all three cell cycle checkpoints after DNA double-stranded break (DSB) damage. H2AX, NBS1, and p53 are substrates of ATM kinase and are involved in ATM-dependent DNA damage responses. We show here that H2AX is dispensable for the activation of ATM and p53 responses after DNA DSB damage. Therefore, H2AX functions primarily as a downstream mediator of ATM functions in the parallel pathway of p53. NBS1 appears to function both as an activator of ATM and as an adapter to mediate ATM activities after DNA DSB damage. Phosphorylation of ATM and H2AX induced by DNA DSB damage is normal in NBS1 mutant/mutant (NBS1m/m) mice that express an N-terminally truncated NBS1 at lower levels. Therefore, the pleiotropic A-T-related systemic and cellular defects observed in NBS1 m/m mice are due to the disruption of the adapter function of NBS1 in mediating ATM activities. While H2AX is required for the irradiation-induced focus formation of NBS1, our findings indicate that NBS1 and H2AX have distinct roles in DNA damage responses. ATM-dependent phosphorylation of p53 and p53 responses are largely normal in NBS1m/m mice after DNA DSB damage, and p53 deficiency greatly facilitates tumorigenesis in NBS1m/m mice. Therefore, NBS1, H2AX, and p53 play synergistic roles in ATM-dependent DNA damage responses and tumor suppression.

Original languageEnglish
Pages (from-to)661-670
Number of pages10
JournalMolecular and Cellular Biology
Volume25
Issue number2
DOIs
Publication statusPublished - 2005 Jan
Externally publishedYes

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Double-Stranded DNA Breaks
DNA Damage
Neoplasms
Phosphotransferases
Phosphorylation
Ataxia Telangiectasia
Cell Cycle Checkpoints
Carcinogenesis

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cell Biology

Cite this

Functional interaction of H2AX, NBS1, and p53 in ATM-dependent DNA damage responses and tumor suppression. / Kang, Jian; Ferguson, David; Song, Hoseok; Bassing, Craig; Eckersdorff, Mark; Alt, Frederick W.; Xu, Yang.

In: Molecular and Cellular Biology, Vol. 25, No. 2, 01.2005, p. 661-670.

Research output: Contribution to journalArticle

Kang, Jian ; Ferguson, David ; Song, Hoseok ; Bassing, Craig ; Eckersdorff, Mark ; Alt, Frederick W. ; Xu, Yang. / Functional interaction of H2AX, NBS1, and p53 in ATM-dependent DNA damage responses and tumor suppression. In: Molecular and Cellular Biology. 2005 ; Vol. 25, No. 2. pp. 661-670.
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