title: A function for cyclin D1 in DNA repair uncovered by protein interactome analyses in human cancers.
abstract: Cyclin D1 is a component of the core cell cycle machinery. Abnormally high levels of cyclin D1 are detected in many human cancer types. 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 process. 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 proliferation. 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.
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Siwanon
authors.initials: S
authors.lastname: Jirawatnotai
authors.forename: Yiduo
authors.initials: Y
authors.lastname: Hu
authors.forename: Wojciech
authors.initials: W
authors.lastname: Michowski
authors.forename: Joshua E
authors.initials: JE
authors.lastname: Elias
authors.forename: Lisa
authors.initials: L
authors.lastname: Becks
authors.forename: Frederic
authors.initials: F
authors.lastname: Bienvenu
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Zagozdzon
authors.forename: Tapasree
authors.initials: T
authors.lastname: Goswami
authors.forename: Yaoyu E
authors.initials: YE
authors.lastname: Wang
authors.forename: Alan B
authors.initials: AB
authors.lastname: Clark
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Kunkel
authors.forename: Tanja
authors.initials: T
authors.lastname: van Harn
authors.forename: Bing
authors.initials: B
authors.lastname: Xia
authors.forename: Mick
authors.initials: M
authors.lastname: Correll
authors.forename: John
authors.initials: J
authors.lastname: Quackenbush
authors.forename: David M
authors.initials: DM
authors.lastname: Livingston
authors.forename: Steven P
authors.initials: SP
authors.lastname: Gygi
authors.forename: Piotr
authors.initials: P
authors.lastname: Sicinski
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D020552:Comet Assay; D019938:Cyclin D1 / Q000172:deficiency / Q000378:metabolism*; D004249:DNA Damage / Q000528:radiation effects; D004260:DNA Repair / Q000528:radiation effects; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding / Q000528:radiation effects; D025941:Protein Interaction Mapping; D051135:Rad51 Recombinase / Q000378:metabolism*; D011839:Radiation, Ionizing; D011995:Recombination, Genetic / Q000235:genetics; D016160:Retinoblastoma Protein / Q000172:deficiency
chemical_list: D016160:Retinoblastoma Protein; D019938:Cyclin D1; C495153:RAD51 protein, human; D051135:Rad51 Recombinase