ATM- and ATR-mediated phosphorylation of XRCC3 regulates DNA double-strand break-induced checkpoint activation and repair

Somyajit, Kumar and Basavaraju, Shivakumar and Scully, Ralph and Nagaraju, Ganesh (2013) ATM- and ATR-mediated phosphorylation of XRCC3 regulates DNA double-strand break-induced checkpoint activation and repair. In: Molecular and Cellular Biology, 33 (9). pp. 1830-1844.

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Abstract

The RAD51 paralogs XRCC3 and RAD51C have been implicated in homologous recombination (HR) and DNA damage responses. However, the molecular mechanism(s) by which these paralogs regulate HR and DNA damage signaling remains obscure. Here, we show that an SQ motif serine 225 in XRCC3 is phosphorylated by ATR kinase in an ATM signaling pathway. We find that RAD51C but not XRCC2 is essential for XRCC3 phosphorylation, and this modification follows end resection and is specific to S and G(2) phases. XRCC3 phosphorylation is required for chromatin loading of RAD51 and HR-mediated repair of double-strand breaks (DSBs). Notably, in response to DSBs, XRCC3 participates in the intra-S-phase checkpoint following its phosphorylation and in the G(2)/M checkpoint independently of its phosphorylation. Strikingly, we find that XRCC3 distinctly regulates recovery of stalled and collapsed replication forks such that phosphorylation is required for the HR-mediated recovery of collapsed replication forks but is dispensable for the restart of stalled replication forks. Together, these findings suggest that XRCC3 is a new player in the ATM/ATR-induced DNA damage responses to control checkpoint and HR-mediated repair.

Item Type:	Journal Article
Publication:	Molecular and Cellular Biology
Publisher:	American Society for Microbiology
Additional Information:	Copyright of this article belongs to American Society for Microbiology.
Department/Centre:	Division of Biological Sciences > Biochemistry
Date Deposited:	31 May 2013 11:58
Last Modified:	31 May 2013 11:58
URI:	http://eprints.iisc.ac.in/id/eprint/46514

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