TY - JOUR
T1 - Double-strand break repair-independent role for BRCA2 in blocking stalled replication fork degradation by MRE11
AU - Schlacher, Katharina
AU - Christ, Nicole
AU - Siaud, Nicolas
AU - Egashira, Akinori
AU - Wu, Hong
AU - Jasin, Maria
N1 - Funding Information:
We thank Francesca Cole, Jeannine LaRocque, Koji Nakanishi, Yu Zhang, and other members of the Jasin lab and for reagents and discussions, Marie-Emilie Terret (MSKCC) and Margaret Leversha (MSKCC) for technical assistance, Julia Sidorova (Seattle) for critical discussions along with Duncan Wright (MSKCC) and Reginald Hill (UCLA), and Toshiyasu Taniguchi (Seattle), Ouathek Ouerfelli (MSKCC), and Berry Sleckman (St. Louis) for reagents. K.S. is the Berger Foundation Fellow of the Damon Runyon Cancer Research Foundation (DRG 1957-07). This work was supported by Susan G. Komen grant BCTR122106 (M.J.) and NIH grants R01CA121110 (H.W.) and R01GM54668 and P01CA94060 (M.J.).
PY - 2011/5/13
Y1 - 2011/5/13
N2 - 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.
AB - 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.
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U2 - 10.1016/j.cell.2011.03.041
DO - 10.1016/j.cell.2011.03.041
M3 - Article
C2 - 21565612
AN - SCOPUS:79955799175
SN - 0092-8674
VL - 145
SP - 529
EP - 542
JO - Cell
JF - Cell
IS - 4
ER -