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PMID: 22789542 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

Cancer cell ·Vol. 22 ·No. 1 ·2012-07-10 ·Pages 106-16

Schlacher K, Wu H, Jasin M

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.

MeSH Terms
BRCA2 Protein/genetics Cell Line, Transformed DNA Replication Fanconi Anemia/genetics Genes, BRCA1 Genes, BRCA2 Genomic Instability Humans Rad51 Recombinase/metabolism
Chemicals
BRCA2 Protein BRCA2 protein, human RAD51 protein, human Rad51 Recombinase
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Schlacher Katharina
Developmental Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA. [email protected]
Wu Hong
Jasin Maria
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Article Info
Journal
Cancer cell
Abbr.
Cancer Cell
ISSN
1878-3686
DOI
10.1016/j.ccr.2012.05.015
Email
[email protected]
Published
2012-07-10
Pages
106-16
Language
English
Region
United States
NLM ID
101130617
PMCID
PMC3954744
Subset
IM
Grants
NCI NIH HHS · P01CA94060 · United States
NCI NIH HHS · R01 CA121110 · United States
NCI NIH HHS · R01CA121110 · United States
NIGMS NIH HHS · R01 GM054668 · United States
NCI NIH HHS · P01 CA094060 · United States
NIGMS NIH HHS · R01GM54668 · United States
Corrections
CommentIn
PMID: 22789533
External Links
PubMed source DOI: 10.1016/j.ccr.2012.05.015 PMC Full Text View journal details
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