CDK-dependent phosphorylation of BRCA2 as a regulatory mechanism for recombinational repair.
Inherited mutations in BRCA2 are associated with a predisposition to early-onset breast cancers. The underlying basis of tumorigenesis is thought to be linked to defects in DNA double-strand break repair by homologous recombination. Here we show that the carboxy-terminal region of BRCA2, which interacts directly with the essential recombination protein RAD51, contains a site (serine 3291; S3291) that is phosphorylated by cyclin-dependent kinases. Phosphorylation of S3291 is low in S phase when recombination is active, but increases as cells progress towards mitosis. This modification blocks C-terminal interactions between BRCA2 and RAD51. However, DNA damage overcomes cell cycle regulation by decreasing S3291 phosphorylation and stimulating interactions with RAD51. These results indicate that S3291 phosphorylation might provide a molecular switch to regulate RAD51 recombination activity, providing new insight into why BRCA2 C-terminal deletions lead to radiation sensitivity and cancer predisposition.
Esashi
Fumiko
F
Cancer Research UK, London Research Institute, Clare Hall Laboratories, South Mimms, Hertfordshire EN6 3LD, UK.
Christ
Nicole
N
Gannon
Julian
J
Liu
Yilun
Y
Hunt
Tim
T
Jasin
Maria
M
West
Stephen C
SC
D000595:Amino Acid Sequence; D000818:Animals; D024682:BRCA2 Protein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology; D002460:Cell Line; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D004249:DNA Damage / Q000235:genetics; D004260:DNA Repair / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D019913:Nuclear Localization Signals; D010766:Phosphorylation; D011485:Protein Binding; D051135:Rad51 Recombinase; D011995:Recombination, Genetic / Q000235:genetics*; D017384:Sequence Deletion / Q000235:genetics
D024682:BRCA2 Protein; D004268:DNA-Binding Proteins; D019913:Nuclear Localization Signals; D018844:Cyclin-Dependent Kinases; C495153:RAD51 protein, human; D051135:Rad51 Recombinase