Atr/atm-mediated phosphorylation of brca1 t1394 promotes homologous recombinational repair and g2-m checkpoint maintenance

Tzeh K. Foo, Gabriele Vincelli, Eric Huselid, Joonyoung Her, Haiyan Zheng, Srilatha Simhadri, Meiling Wang, Yanying Huo, Tao Li, Xiaochun Yu, Hong Li, Weixing Zhao, Samuel F. Bunting, Bing Xia

Research output: Contribution to journalArticlepeer-review

Abstract

BRCA1 maintains genome integrity and suppresses tumorigenesis by promoting homologous recombination (HR)-mediated repair of DNA double-strand breaks (DSB) and DNA damageinduced cell-cycle checkpoints. Phosphorylation of BRCA1 by ATM, ATR, CHK2, CDK, and PLK1 kinases has been reported to regulate its functions. Here we show that ATR and ATM-mediated phosphorylation of BRCA1 on T1394, a highly conserved but functionally uncharacterized site, is a key modification for its function in the DNA damage response (DDR). Following DNA damage, T1394 phosphorylation ensured faithful repair of DSBs by promoting HR and preventing single-strand annealing, a deletiongenerating repair process. BRCA1 T1394 phosphorylation further safeguarded chromosomal integrity by maintaining the G2-M checkpoint. Moreover, multiple patient-derived BRCA1 variants of unknown significance were shown to affect T1394 phosphorylation. These results establish an important regulatory mechanism of BRCA1 function in the DDR and may have implications in the development or prognosis of BRCA1-associated cancers.

Original languageEnglish (US)
Pages (from-to)4676-4684
Number of pages9
JournalCancer Research
Volume81
Issue number18
DOIs
StatePublished - Sep 15 2021

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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