BRCA1 modulates the autophosphorylation status of DNA-PKcs in S phase of the cell cycle

Anthony J. Davis, Linfeng Chi, Sairei So, Kyung Jong Lee, Eiichiro Mori, Kazi Fattah, Jun Yang, David J. Chen

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Non-homologous end-joining (NHEJ) and homologous recombination (HR) are the two prominent pathways responsible for the repair of DNA double-strand breaks (DSBs). NHEJ is not restricted to a cell-cycle stage, whereas HR is active primarily in the S/G2 phases suggesting there are cell cycle-specific mechanisms that play a role in the choice between NHEJ and HR. Here we show NHEJ is attenuated in S phase via modulation of the autophosphorylation status of the NHEJ factor DNA-PKcs at serine 2056 by the pro-HR factor BRCA1. BRCA1 interacts with DNA-PKcs in a cell cycle-regulated manner and this interaction is mediated by the tandem BRCT domain of BRCA1, but surprisingly in a phospho-independent manner. BRCA1 attenuates DNA-PKcs autophosphorylation via directly blocking the ability of DNA-PKcs to autophosphorylate. Subsequently, blocking autophosphorylation of DNA-PKcs at the serine 2056 phosphorylation cluster promotes HR-required DNA end processing and loading of HR factors to DSBs and is a possible mechanism by which BRCA1 promotes HR.

Original languageEnglish (US)
Pages (from-to)11487-11501
Number of pages15
JournalNucleic Acids Research
Volume42
Issue number18
DOIs
StatePublished - Sep 12 2014

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Homologous Recombination
S Phase
Cell Cycle
DNA
Serine
DNA End-Joining Repair
Double-Stranded DNA Breaks
G2 Phase
Phosphorylation

ASJC Scopus subject areas

  • Genetics
  • Medicine(all)

Cite this

BRCA1 modulates the autophosphorylation status of DNA-PKcs in S phase of the cell cycle. / Davis, Anthony J.; Chi, Linfeng; So, Sairei; Lee, Kyung Jong; Mori, Eiichiro; Fattah, Kazi; Yang, Jun; Chen, David J.

In: Nucleic Acids Research, Vol. 42, No. 18, 12.09.2014, p. 11487-11501.

Research output: Contribution to journalArticle

Davis, Anthony J. ; Chi, Linfeng ; So, Sairei ; Lee, Kyung Jong ; Mori, Eiichiro ; Fattah, Kazi ; Yang, Jun ; Chen, David J. / BRCA1 modulates the autophosphorylation status of DNA-PKcs in S phase of the cell cycle. In: Nucleic Acids Research. 2014 ; Vol. 42, No. 18. pp. 11487-11501.
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