A function for cyclin D1 in DNA repair uncovered by protein interactome analyses in human cancers.
A function for cyclin D1 in DNA repair uncovered by protein interactome analyses in human cancers.
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DOI：
10.1038/nature10155
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发表时间：
2011-06-08
期刊：
影响因子：
64.8
通讯作者：
Sicinski P
中科院分区：
文献类型：
--
作者：
Jirawatnotai S;Hu Y;Michowski W;Elias JE;Becks L;Bienvenu F;Zagozdzon A;Goswami T;Wang YE;Clark AB;Kunkel TA;van Harn T;Xia B;Correll M;Quackenbush J;Livingston DM;Gygi SP;Sicinski P
细胞周期蛋白D1是核心细胞周期机制的组成部分。在许多人类癌症类型中检测到异常高水平的细胞周期蛋白D1。为了阐明细胞周期蛋白D1在人类癌症中的分子功能，我们在几种类型的人类肿瘤中进行了细胞周期蛋白D1蛋白伴侣的蛋白质组学筛选。对细胞周期蛋白D1-interactors的分析揭示了DNA修复蛋白的网络，包括RAD51，一种驱动同源重组过程的重组酶。我们发现，细胞周期蛋白D1直接结合RAD51，和细胞周期蛋白D1-RAD51的相互作用是由辐射诱导。像RAD51一样，细胞周期蛋白D1以BRCA2依赖的方式被募集到DNA损伤位点。人癌细胞中细胞周期蛋白D1水平的降低损害了RAD51对受损DNA的募集，阻碍了同源重组介导的DNA修复，并增加了细胞对体外和体内辐射的敏感性。这种效应在缺乏视网膜母细胞瘤蛋白的癌细胞中观察到，这些癌细胞不需要D-细胞周期蛋白进行增殖。这些发现揭示了核心细胞周期蛋白在DNA修复中的意想不到的功能，并表明靶向细胞周期蛋白D1可能对视网膜母细胞瘤阴性癌症也有益，目前认为这些癌症对细胞周期蛋白D1抑制作用不敏感。
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, here we performed a proteomic screen for cyclin D1 protein partners in several types of human tumors. 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 oblivious to cyclin D1 inhibition.