The BRCT Domains of the BRCA1 and BARD1 Tumor Suppressors Differentially Regulate Homology-Directed Repair and Stalled Fork Protection

Overview

Journal Mol Cell

Publisher Cell Press

Specialty Cell Biology

Date 2018 Sep 25

PMID 30244837

Citations 45

Authors

David Billing

Michiko Horiguchi

Foon Wu-Baer

Angelo Taglialatela

Giuseppe Leuzzi

Silvia Alvarez Nanez

Wenxia Jiang

Shan Zha

Matthias Szabolcs

Chyuan-Sheng Lin

Alberto Ciccia

Richard Baer

Affiliations

Soon will be listed here.

Abstract

The BRCA1 tumor suppressor preserves genome integrity through both homology-directed repair (HDR) and stalled fork protection (SFP). In vivo, BRCA1 exists as a heterodimer with the BARD1 tumor suppressor, and both proteins harbor a phosphate-binding BRCT domain. Here, we compare mice with mutations that ablate BRCT phospho-recognition by Bard1 (Bard1 and Bard1) or Brca1 (Brca1). Brca1 abrogates both HDR and SFP, suggesting that both pathways are likely impaired in most BRCA1 mutant tumors. Although not affecting HDR, the Bard1 mutations ablate poly(ADP-ribose)-dependent recruitment of BRCA1/BARD1 to stalled replication forks, resulting in fork degradation and chromosome instability. Nonetheless, Bard1 and Bard1 mice, unlike Brca1 mice, are not tumor prone, indicating that HDR alone is sufficient to suppress tumor formation in the absence of SFP. Nevertheless, because SFP, unlike HDR, is also impaired in heterozygous Brca1/Bard1 mutant cells, SFP and HDR may contribute to distinct stages of tumorigenesis in BRCA1/BARD1 mutation carriers.

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