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Cyclin D1 promotes BRCA2-Rad51 interaction by restricting cyclin A/B-dependent BRCA2 phosphorylation

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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.

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Acknowledgements

We thank Dr Piotr Sicinski, Dana-Farber Cancer Institute, in whose laboratory this work was initiated. This study was supported by Thailand Research Fund RSA5580018, Siriraj Research Fund, Faculty of Medicine Siriraj Hospital, Mahidol University, and the Advanced Research on Pharmacology Fund, Siriraj Foundation D003421. SJ was supported by the Chalermphrakiat Grant, Faculty of Medicine Siriraj Hospital, Mahidol University.

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Authors and Affiliations

  1. Department of Pharmacology, Laboratory for Systems Pharmacology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand

    C Chalermru**anant, G Sittithumcharee & S Jirawatnotai

  2. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA

    W Michowski & S Jirawatnotai

  3. The Sir William Dunn School of Pathology, University of Oxford, Oxford, UK

    F Esashi

  4. Institute of Molecular Biosciences, Mahidol University, Bangkok, Thailand

    S Jirawatnotai

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  1. C Chalermru**anant
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Correspondence to S Jirawatnotai.

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Chalermru**anant, C., Michowski, W., Sittithumcharee, G. et al. Cyclin D1 promotes BRCA2-Rad51 interaction by restricting cyclin A/B-dependent BRCA2 phosphorylation. Oncogene 35, 2815–2823 (2016). https://doi.org/10.1038/onc.2015.354

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