Oncogenic Ras Regulates BRIP1 Expression to Induce Dissociation of BRCA1 from Chromatin, Inhibit DNA Repair, and Promote Senescence

Zhigang Tu, Katherine M. Aird, Benjamin G. Bitler, Jasmine P. Nicodemus, Neil Beeharry, Bing Xia, Tim J. Yen, Rugang Zhang

Research output: Contribution to journalArticlepeer-review

58 Scopus citations

Abstract

Here, we report a cell-intrinsic mechanism by which oncogenic RAS promotes senescence while predisposing cells to senescence bypass by allowing for secondary hits. We show that oncogenic RAS inactivates the BRCA1 DNA repair complex by dissociating BRCA1 from chromatin. This event precedes senescence-associated cell cycle exit and coincides with the accumulation of DNA damage. Downregulation of BRIP1, a physiological partner of BRCA1 in the DNA repair pathway, triggers BRCA1 chromatin dissociation. Conversely, ectopic BRIP1 rescues BRCA1 chromatin dissociation and suppresses RAS-induced senescence and the DNA damage response. Significantly, cells undergoing senescence do not exhibit a BRCA1-dependent DNA repair response when exposed to DNA damage. Overall, our study provides a molecular basis by which oncogenic RAS promotes senescence. Because DNA damage has the potential to produce additional " hits" that promote senescence bypass, our findings may also suggest one way a small minority of cells might bypass senescence and contribute to cancer development.

Original languageEnglish (US)
Pages (from-to)1077-1091
Number of pages15
JournalDevelopmental Cell
Volume21
Issue number6
DOIs
StatePublished - Dec 13 2011

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Developmental Biology
  • Cell Biology

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