Damage-induced BRCA1 phosphorylation by Chk2 contributes to the timing of end resection

Balaji Parameswaran, Huai Chin Chiang, Yunzhe Lu, Julia Coates, Chu Xia Deng, Richard Baer, Hui Kuan Lin, Rong Li, Tanya T. Paull, Yanfen Hu

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

The BRCA1 tumor suppressor plays an important role in homologous recombination (HR)-mediated DNA doublestrand- break (DSB) repair. BRCA1 is phosphorylated by Chk2 kinase upon g-irradiation, but the role of Chk2 phosphorylation is not understood. Here, we report that abrogation of Chk2 phosphorylation on BRCA1 delays end resection and the dispersion of BRCA1 from DSBs but does not affect the assembly of Mre11/Rad50/NBS1 (MRN) and CtIP at DSBs. Moreover, we show that BRCA1 is ubiquitinated by SCFSkp2 and that abrogation of Chk2 phosphorylation impairs its ubiquitination. Our study suggests that BRCA1 is more than a scaffold protein to assemble HR repair proteins at DSBs, but that Chk2 phosphorylation of BRCA1 also serves as a built-in clock for HR repair of DSBs. BRCA1 is known to inhibit Mre11 nuclease activity. SCFSkp2 activity appears at late G1 and peaks at S/G2, and is known to ubiquitinate phosphodegron motifs. The removal of BRCA1 from DSBs by SCFSkp2-mediated degradation terminates BRCA1- mediated inhibition of Mre11 nuclease activity, allowing for end resection and restricting the initiation of HR to the S/ G2 phases of the cell cycle.

Original languageEnglish (US)
Pages (from-to)437-448
Number of pages12
JournalCell Cycle
Volume14
Issue number3
DOIs
StatePublished - Feb 1 2015

Keywords

  • BRCA1
  • Cell cycle
  • DNA double-strand break repair
  • End-resection
  • SCF

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology
  • Cell Biology

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  • Cite this

    Parameswaran, B., Chiang, H. C., Lu, Y., Coates, J., Deng, C. X., Baer, R., Lin, H. K., Li, R., Paull, T. T., & Hu, Y. (2015). Damage-induced BRCA1 phosphorylation by Chk2 contributes to the timing of end resection. Cell Cycle, 14(3), 437-448. https://doi.org/10.4161/15384101.2014.972901