A dual role of BRCA1 in two distinct homologous recombination mediated repair in response to replication arrest
Open Access
- 27 September 2011
- journal article
- research article
- Published by Oxford University Press (OUP) in Nucleic Acids Research
- Vol. 40 (2), 726-738
- https://doi.org/10.1093/nar/gkr748
Abstract
Homologous recombination (HR) is a major mechanism utilized to repair blockage of DNA replication forks. Here, we report that a sister chromatid exchange (SCE) generated by crossover-associated HR efficiently occurs in response to replication fork stalling before any measurable DNA double-strand breaks (DSBs). Interestingly, SCE produced by replication fork collapse following DNA DSBs creation is specifically suppressed by ATR, a central regulator of the replication checkpoint. BRCA1 depletion leads to decreased RPA2 phosphorylation (RPA2-P) following replication fork stalling but has no obvious effect on RPA2-P following replication fork collapse. Importantly, we found that BRCA1 promotes RAD51 recruitment and SCE induced by replication fork stalling independent of ATR. In contrast, BRCA1 depletion leads to a more profound defect in RAD51 recruitment and SCE induced by replication fork collapse when ATR is depleted. We concluded that BRCA1 plays a dual role in two distinct HR-mediated repair upon replication fork stalling and collapse. Our data established a molecular basis for the observation that defective BRCA1 leads to a high sensitivity to agents that cause replication blocks without being associated with DSBs, and also implicate a novel mechanism by which loss of cell cycle checkpoints promotes BRCA1-associated tumorigenesis via enhancing HR defect resulting from BRCA1 deficiency.Funding Information
- National Cancer Institute
- Wendy Will Case Cancer Fund
- American Cancer Society
This publication has 57 references indexed in Scilit:
- 53BP1 loss rescues BRCA1 deficiency and is associated with triple-negative and BRCA-mutated breast cancersNature Structural & Molecular Biology, 2010
- 53BP1 Inhibits Homologous Recombination in Brca1-Deficient Cells by Blocking Resection of DNA BreaksCell, 2010
- Mitotic homologous recombination maintains genomic stability and suppresses tumorigenesisNature Reviews Molecular Cell Biology, 2010
- Hydroxyurea-Stalled Replication Forks Become Progressively Inactivated and Require Two Different RAD51-Mediated Pathways for Restart and RepairMolecular Cell, 2010
- A Selective Requirement for 53BP1 in the Biological Response to Genomic Instability Induced by Brca1 DeficiencyMolecular Cell, 2009
- CtIP-BRCA1 modulates the choice of DNA double-strand-break repair pathway throughout the cell cycleNature, 2009
- Differential regulation of homologous recombination at DNA breaks and replication forks by the Mrc1 branch of the S-phase checkpointThe EMBO Journal, 2009
- Rad52 recruitment is DNA replication independent and regulated by Cdc28 and the Mec1 kinaseThe EMBO Journal, 2009
- Human CtIP promotes DNA end resectionNature, 2007
- The structure-specific endonuclease Mus81–Eme1 promotes conversion of interstrand DNA crosslinks into double-strands breaksThe EMBO Journal, 2006