Association of BRCA1 with the hRad50-hMre11-p95 complex and the DNA damage response.
BRCA1 encodes a tumor suppressor that is mutated in familial breast and ovarian cancers. Here, it is shown that BRCA1 interacts in vitro and in vivo with hRad50, which forms a complex with hMre11 and p95/nibrin. Upon irradiation, BRCA1 was detected in discrete foci in the nucleus, which colocalize with hRad50. Formation of irradiation-induced foci positive for BRCA1, hRad50, hMre11, or p95 was dramatically reduced in HCC/1937 breast cancer cells carrying a homozygous mutation in BRCA1 but was restored by transfection of wild-type BRCA1. Ectopic expression of wild-type, but not mutated, BRCA1 in these cells rendered them less sensitive to the DNA damage agent, methyl methanesulfonate. These data suggest that BRCA1 is important for the cellular responses to DNA damage that are mediated by the hRad50-hMre11-p95 complex.
Zhong
Q
Q
Department of Molecular Medicine, Institute of Biotechnology, University of Texas Health Science Center at San Antonio, 15355 Lambda Drive, San Antonio, TX 78245, USA.
Chen
C F
CF
Li
S
S
Chen
Y
Y
Wang
C C
CC
Xiao
J
J
Chen
P L
PL
Sharp
Z D
ZD
Lee
W H
WH
D017766:Acid Anhydride Hydrolases; D019313:BRCA1 Protein / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism*; D002470:Cell Survival; D004249:DNA Damage; D045643:DNA Repair Enzymes; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005720:Gamma Rays; D019398:Genes, BRCA1; D006801:Humans; D000076228:MRE11 Homologue Protein; D008741:Methyl Methanesulfonate / Q000494:pharmacology; D009153:Mutagens / Q000494:pharmacology; D009154:Mutation; D009687:Nuclear Proteins; D051135:Rad51 Recombinase; D011995:Recombination, Genetic; D014162:Transfection; D014407:Tumor Cells, Cultured
D019313:BRCA1 Protein; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C121766:MRE11 protein, human; D009153:Mutagens; C112156:NBN protein, human; D009687:Nuclear Proteins; D008741:Methyl Methanesulfonate; C495153:RAD51 protein, human; D051135:Rad51 Recombinase; D000076228:MRE11 Homologue Protein; D017766:Acid Anhydride Hydrolases; C112158:RAD50 protein, human; D045643:DNA Repair Enzymes