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Cancer Cell. 2012 Jul 10;22(1):106-16. doi: 10.1016/j.ccr.2012.05.015.

A distinct replication fork protection pathway connects Fanconi anemia tumor suppressors to RAD51-BRCA1/2.

Author information

1
Developmental Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA. schlachk@mskcc.org

Abstract

Genes mutated in patients with Fanconi anemia (FA) interact with the DNA repair genes BRCA1 and BRCA2/FANCD1 to suppress tumorigenesis, but the molecular functions ascribed to them cannot fully explain all of their cellular roles. Here, we show a repair-independent requirement for FA genes, including FANCD2, and BRCA1 in protecting stalled replication forks from degradation. Fork protection is surprisingly rescued in FANCD2-deficient cells by elevated RAD51 levels or stabilized RAD51 filaments. Moreover, FANCD2-mediated fork protection is epistatic with RAD51 functions, revealing an unanticipated fork protection pathway that connects FA genes to RAD51 and the BRCA1/2 breast cancer suppressors. Collective results imply a unified molecular mechanism for repair-independent functions of FA, RAD51, and BRCA1/2 proteins in preventing genomic instability and suppressing tumorigenesis.

PMID:
22789542
PMCID:
PMC3954744
DOI:
10.1016/j.ccr.2012.05.015
[Indexed for MEDLINE]
Free PMC Article

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