Phosphorylation of BRCA2 by the Polo-like kinase Plk1 is regulated by DNA damage and mitotic progression.
The breast cancer susceptibility protein, BRCA2, preserves chromosomal stability through roles in the repair of DNA double-strand breaks, and possibly, cell division. Post-translational modifications that may coordinate these functions remain poorly characterized. Here, we report that BRCA2 is a substrate for the mitotic Polo-like kinase, Plk1. BRCA2 undergoes phosphorylation in cells synchronously passing through the G2/M phases of cell cycle, when Plk1 expression and activity are maximal. Depletion of Plk1 by RNA interference suppresses BRCA2 modification. BRCA2 and Plk1 interact with one another in cell lysates, through a conserved region in BRCA2, which spans the eight BRC repeat motifs essential for its function in DNA repair. Within this region, residues positioned between BRC repeats--but not the repeat motifs themselves--are phosphorylated by Plk1. Interestingly, Plk1-mediated modification of BRCA2 during the G2/M phases is inhibited by treatment with the radiomimetic agent, adriamycin. Thus, our findings define a regulatory circuit for BRCA2 phosphorylation by Plk1 that is responsive to DNA damage as well as mitotic progression.
Lee
MiYoung
M
CR UK Department of Oncology and the Medical Research Council Cancer Cell Unit, Hutchison/MRC Research Centre, University of Cambridge, Hills Road, Cambridge CB2 2XZ, UK.
Daniels
Matthew J
MJ
Venkitaraman
Ashok R
AR
D024682:BRCA2 Protein / Q000378:metabolism*; D001483:Base Sequence; D015153:Blotting, Western; D018797:Cell Cycle Proteins; D002460:Cell Line; D004249:DNA Damage; D017931:DNA Primers; D006801:Humans; D008938:Mitosis; D010766:Phosphorylation; D011494:Protein Kinases / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D000097869:Polo-Like Kinase 1
D024682:BRCA2 Protein; D018797:Cell Cycle Proteins; D017931:DNA Primers; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D000097869:Polo-Like Kinase 1