DNA Damage-Induced Cell Cycle Checkpoint Control Requires CtIP, a Phosphorylation-Dependent Binding Partner of BRCA1 C-Terminal Domains

Abstract

The BRCA1 C-terminal (BRCT) domain has recently been implicated as a phospho-protein binding domain. We demonstrate here that a CTBP-interacting protein CtIP interacts with BRCA1 BRCT domains in a phosphorylation-dependent manner. The CtIP/BRCA1 complex only exists in G₂ phase and is required for DNA damage-induced Chk1 phosphorylation and the G₂/M transition checkpoint. However, the CtIP/BRCA1 complex is not required for the damage-induced G₂ accumulation checkpoint, which is controlled by a separate BRCA1/BACH1 complex. Taken together, these data not only implicate CtIP as a critical player in cell cycle checkpoint control but also provide molecular mechanisms by which BRCA1 controls multiple cell cycle transitions after DNA damage.

We thank D. M. Livingston and R. Baer for valuable reagents. We thank Carolin Merkle and Katherine Minter-Dykhouse for proofreading the manuscript.

This study is supported in part by grants from the National Institutes of Health (CA89239 and CA92312), the Prospect Creek Foundation, and the Breast Cancer Research Foundation. J.C. received a DOD breast cancer career development award (DAMD17-02-1-0472).