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Title: A function for cyclin D1 in DNA repair uncovered by protein interactome analyses in human cancers
Authors: Siwanon Jirawatnotai
Yiduo Hu
Wojciech Michowski
Joshua E. Elias
Lisa Becks
Frederic Bienvenu
Agnieszka Zagozdzon
Tapasree Goswami
Yaoyu E. Wang
Alan B. Clark
Thomas A. Kunkel
Tanja Van Harn
Bing Xia
Mick Correll
John Quackenbush
David M. Livingston
Steven P. Gygi
Piotr Sicinski
Harvard Medical School
Mahidol University
Massachusetts College of Pharmacy and Health Sciences
Dana-Farber Cancer Institute
National Institutes of Health, Bethesda
Rutgers Robert Wood Johnson Medical School at New Brunswick
Harvard School of Public Health
Stanford University School of Medicine
Universite de Montpellier
Keywords: Multidisciplinary
Issue Date: 8-Jun-2011
Citation: Nature. Vol.474, No.7350 (2011), 230-234
Abstract: Cyclin D1 is a component of the core cell cycle machinery 1 . Abnormally high levels of cyclin D1 are detected in many human cancer types 2 . 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. © 2011 Macmillan Publishers Limited. All rights reserved.
ISSN: 14764687
Appears in Collections:Scopus 2011-2015

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