A function for cyclin D1 in DNA repair uncovered by protein interactome analyses in human cancers

Abstract

Cyclin D1 has a crucial role in the cell cycle and is often overexpressed in cancer. Piotr Sicinski and colleagues report an unexpected function for cyclin D1 in DNA repair that is independent of its known CDK-dependent role. Cyclin D1 is recruited to sites of DNA damage and binds to RAD51, a key DNA recombinase that drives the homologous recombination process. This function for cyclin D1 also operates in retinoblastoma protein (pRB)-negative human cancer, suggesting that targeting cyclin D1 may be beneficial in this condition. Cyclin D1 is a component of the core cell cycle machinery1. Abnormally high levels of cyclin D1 are detected in many human cancer types2. To elucidate the molecular functions of cyclin D1 in human cancers, we performed a proteomic screen for cyclin D1 protein partners in several types of human tumours. Analyses of cyclin D1 interactors revealed a network of DNA repair proteins, including RAD51, a recombinase that drives the homologous recombination process3. We found that cyclin D1 directly binds RAD51, and that cyclin D1–RAD51 interaction is induced by radiation. Like RAD51, cyclin D1 is recruited to DNA damage sites in a BRCA2-dependent fashion. Reduction of cyclin D1 levels in human cancer cells impaired recruitment of RAD51 to damaged DNA, impeded the homologous recombination-mediated DNA repair, and increased sensitivity of cells to radiation in vitro and in vivo. This effect was seen in cancer cells lacking the retinoblastoma protein, which do not require D-cyclins for proliferation4,5. These findings reveal an unexpected function of a core cell cycle protein in DNA repair and suggest that targeting cyclin D1 may be beneficial also in retinoblastoma-negative cancers which are currently thought to be unaffected by cyclin D1 inhibition.