Role of BRCA2 in control of the RAD51 recombination and DNA repair protein.
Individuals carrying BRCA2 mutations are predisposed to breast and ovarian cancers. Here, we show that BRCA2 plays a dual role in regulating the actions of RAD51, a protein essential for homologous recombination and DNA repair. First, interactions between RAD51 and the BRC3 or BRC4 regions of BRCA2 block nucleoprotein filament formation by RAD51. Alterations to the BRC3 region that mimic cancer-associated BRCA2 mutations fail to exhibit this effect. Second, transport of RAD51 to the nucleus is defective in cells carrying a cancer-associated BRCA2 truncation. Thus, BRCA2 regulates both the intracellular localization and DNA binding ability of RAD51. Loss of these controls following BRCA2 inactivation may be a key event leading to genomic instability and tumorigenesis.
Davies
A A
AA
Imperial Cancer Research Fund, Clare Hall Laboratories, Hertfordshire EN6 3LD, South Mimms, United Kingdom.
Masson
J Y
JY
McIlwraith
M J
MJ
Stasiak
A Z
AZ
Stasiak
A
A
Venkitaraman
A R
AR
West
S C
SC
D021581:Active Transport, Cell Nucleus; D000595:Amino Acid Sequence; D024682:BRCA2 Protein; D001665:Binding Sites; D001943:Breast Neoplasms / Q000235:genetics; D002850:Chromatography, Gel; D004247:DNA / Q000235:genetics / Q000378:metabolism; D004260:DNA Repair / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D008854:Microscopy, Electron; D008954:Models, Biological; D008969:Molecular Sequence Data; D008970:Molecular Weight; D009154:Mutation; D009363:Neoplasm Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009698:Nucleoproteins / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000648:ultrastructure; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D051135:Rad51 Recombinase; D011995:Recombination, Genetic; D013347:Subcellular Fractions; D013379:Substrate Specificity; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
D024682:BRCA2 Protein; D004268:DNA-Binding Proteins; D009363:Neoplasm Proteins; D009698:Nucleoproteins; D010446:Peptide Fragments; D014157:Transcription Factors; D004247:DNA; C495153:RAD51 protein, human; D051135:Rad51 Recombinase