Double-strand break repair-independent role for BRCA2 in blocking stalled replication fork degradation by MRE11 Journal Article

   

Authors:	Schlacher, K.; Christ, N.; Siaud, N.; Egashira, A.; Wu, H.; Jasin, M.
Article Title:	Double-strand break repair-independent role for BRCA2 in blocking stalled replication fork degradation by MRE11
Abstract:	Breast cancer suppressor BRCA2 is critical for maintenance of genomic integrity and resistance to agents that damage DNA or collapse replication forks, presumably through homology-directed repair of double-strand breaks (HDR). Using single-molecule DNA fiber analysis, we show here that nascent replication tracts created before fork stalling with hydroxyurea are degraded in the absence of BRCA2 but are stable in wild-type cells. BRCA2 mutational analysis reveals that a conserved C-terminal site involved in stabilizing RAD51 filaments, but not in loading RAD51 onto DNA, is essential for this fork protection but dispensable for HDR. RAD51 filament disruption in wild-type cells phenocopies BRCA2 deficiency. BRCA2 prevents chromosomal aberrations on replication stalling, which are alleviated by inhibition of MRE11, the nuclease responsible for this form of fork instability. Thus, BRCA2 prevents rather than repairs nucleolytic lesions at stalled replication forks to maintain genomic integrity and hence likely suppresses tumorigenesis through this replication-specific function. © 2011 Elsevier Inc.
Keywords:	controlled study; hydroxyurea; nonhuman; dna replication; animal cell; mre11 protein; cell survival; dna repair; carboxy terminal sequence; protein degradation; protein stability; protein interaction; mutational analysis; brca2 protein; chromosome aberration; genomic instability; double stranded dna break; genetic conservation; rad51 protein; dna strand
Journal Title:	Cell
Volume:	145
Issue:	4
ISSN:	0092-8674
Publisher:	Cell Press
Date Published:	2011-05-13
Start Page:	529
End Page:	542
Language:	English
DOI:	10.1016/j.cell.2011.03.041
PROVIDER:	scopus
PUBMED:	21565612
PMCID:	PMC3261725
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-79955799175&partnerID=40&md5=51f29ae09edd9db7b252a80f87238212
Notes:	--- - "Export Date: 23 June 2011" - "CODEN: CELLB" - "Source: Scopus"

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