Coupling of Homologous Recombination and the Checkpoint by ATR

Overview

Journal Mol Cell

Publisher Cell Press

Specialty Cell Biology

Date 2017 Jan 17

PMID 28089683

Citations 109

Authors

Remi Buisson

Joshi Niraj

Amelie Rodrigue

Chu Kwen Ho

Johannes Kreuzer

Tzeh Keong Foo

Emilie J-L Hardy

Graham Dellaire

Wilhelm Haas

Bing Xia

Jean-Yves Masson

Lee Zou

Affiliations

Soon will be listed here.

Abstract

ATR is a key regulator of cell-cycle checkpoints and homologous recombination (HR). Paradoxically, ATR inhibits CDKs during checkpoint responses, but CDK activity is required for efficient HR. Here, we show that ATR promotes HR after CDK-driven DNA end resection. ATR stimulates the BRCA1-PALB2 interaction after DNA damage and promotes PALB2 localization to DNA damage sites. ATR enhances BRCA1-PALB2 binding at least in part by inhibiting CDKs. The optimal interaction of BRCA1 and PALB2 requires phosphorylation of PALB2 at S59, an ATR site, and hypo-phosphorylation of S64, a CDK site. The PALB2-S59A/S64E mutant is defective for localization to DNA damage sites and HR, whereas the PALB2-S59E/S64A mutant partially bypasses ATR for its localization. Thus, HR is a biphasic process requiring both high-CDK and low-CDK periods. As exemplified by the regulation of PALB2 by ATR, ATR promotes HR by orchestrating a "CDK-to-ATR switch" post-resection, directly coupling the checkpoint to HR.

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