Cyclin D1 promotes BRCA2-Rad51 interaction by restricting cyclin A/B-dependent BRCA2 phosphorylation.
BRCA2 has an important role in the maintenance of genome stability by interacting with RAD51 recombinase through its C-terminal domain. This interaction is abrogated by cyclin A-CDK2-mediated phosphorylation of BRCA2 at serine 3291 (Ser3291). Recently, we showed that cyclin D1 facilitates RAD51 recruitment to BRCA2-containing DNA repair foci, and that ... downregulation of cyclin D1 leads to inefficient homologous-mediated DNA repair. Here, we demonstrate that cyclin D1, via amino acids 20-90, interacts with the C-terminal domain of BRCA2, and that this interaction is increased in response to DNA damage. Interestingly, CDK4-cyclin D1 does not phosphorylate Ser3291. Instead, cyclin D1 bars cyclin A from the C-terminus of BRCA2, prevents cyclin A-CDK2-dependent Ser3291 phosphorylation and facilitates RAD51 binding to the C-terminal domain of BRCA2. These findings indicate that the interplay between cyclin D1 and other cyclins such as cyclin A regulates DNA integrity through RAD51 interaction with the BRCA2 C-terminal domain.
Mesh Terms:
BRCA2 Protein, Cell Line, Tumor, Cyclin A, Cyclin B, Cyclin D1, Gene Expression Regulation, Neoplastic, Humans, Phosphorylation, Protein Binding, Protein Domains, Rad51 Recombinase
BRCA2 Protein, Cell Line, Tumor, Cyclin A, Cyclin B, Cyclin D1, Gene Expression Regulation, Neoplastic, Humans, Phosphorylation, Protein Binding, Protein Domains, Rad51 Recombinase
Oncogene
Date: Dec. 02, 2015
PubMed ID: 26387543
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