title: Cyclin D1 promotes BRCA2-Rad51 interaction by restricting cyclin A/B-dependent BRCA2 phosphorylation.
abstract: 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.
authors.affiliation: Laboratory for Systems Pharmacology, Department of Pharmacology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
authors.forename: C
authors.initials: C
authors.lastname: Chalermrujinanant
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: W
authors.initials: W
authors.lastname: Michowski
authors.affiliation: Laboratory for Systems Pharmacology, Department of Pharmacology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
authors.forename: G
authors.initials: G
authors.lastname: Sittithumcharee
authors.affiliation: The Sir William Dunn School of Pathology, University of Oxford, Oxford, UK.
authors.forename: F
authors.initials: F
authors.lastname: Esashi
authors.affiliation: Laboratory for Systems Pharmacology, Department of Pharmacology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.|Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.|Institute of Molecular Biosciences, Mahidol University, Bangkok, Thailand.
authors.forename: S
authors.initials: S
authors.lastname: Jirawatnotai
mesh_terms: D024682:BRCA2 Protein / Q000737:chemistry / Q000378:metabolism*; D045744:Cell Line, Tumor; D019925:Cyclin A / Q000378:metabolism*; D019926:Cyclin B / Q000378:metabolism*; D019938:Cyclin D1 / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D010766:Phosphorylation; D011485:Protein Binding; D000072417:Protein Domains; D051135:Rad51 Recombinase / Q000378:metabolism*
chemical_list: D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D019925:Cyclin A; D019926:Cyclin B; D019938:Cyclin D1; D051135:Rad51 Recombinase