Alternative cyclin D1 splice forms differentially regulate the DNA damage response.
Alternative cyclin D1 splice forms differentially regulate the DNA damage response.
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DOI：
10.1158/0008-5472.can-10-0312
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发表时间：
2010-11-01
期刊：
影响因子：
11.2
通讯作者：
Pestell RG
中科院分区：
文献类型：
--
作者：
Li Z;Jiao X;Wang C;Shirley LA;Elsaleh H;Dahl O;Wang M;Soutoglou E;Knudsen ES;Pestell RG
DNA损伤反应（DDR）激活下游途径，包括细胞周期检查点。细胞周期蛋白D1基因在许多人类癌症中过表达或扩增，并且是小鼠模型中胃肠道、乳腺和皮肤肿瘤所需的。人类细胞周期蛋白D1基因的一个常见多态性是选择性剪接，导致细胞周期蛋白D1 a和D1 b蛋白质的羧基末端不同。细胞周期蛋白D1过表达增强DNA损伤诱导的细胞凋亡。细胞周期蛋白D1和选择性剪接形式在调节DDR中的作用还不清楚。细胞周期蛋白D1 a过表达可增强DDR，其特征在于诱导γ H2 AX磷酸化，DNA修复灶的组装，DNA修复因子特异性募集到染色质，以及G2/M期阻滞。成纤维细胞中细胞周期蛋白D1的缺失或siRNA介导的结肠癌细胞中内源性细胞周期蛋白D1的减少减少了5-FU介导的DDR。机制研究表明，细胞周期蛋白D1 a，像DNA修复因子，引发DDR时，稳定地与染色质。
The DNA damage response (DDR) activates downstream pathways including cell cycle checkpoints. The cyclin D1 gene is overexpressed or amplified in many human cancers and is required for gastrointestinal, breast, and skin tumors in murine models. A common polymorphism in the human cyclin D1 gene is alternatively spliced, resulting in cyclin D1a and D1b proteins that differ in their carboxyl terminus. Cyclin D1 overexpression enhances DNA-damage induced apoptosis. The role of cyclin D1 and the alternative splice form in regulating the DDR is not well understood. Herein cyclin D1a overexpression enhanced the DDR as characterized by induction of γH2AX phosphorylation, the assembly of DNA repair foci, and specific recruitment of DNA repair factors to chromatin, and G2/M arrest. Cyclin D1 deletion in fibroblasts or siRNA mediated reduction of endogenous cyclin D1 in colon cancer cells reduced the 5-FU-mediated DDR. Mechanistic studies demonstrated cyclin D1a, like DNA repair factors, elicited the DDR when stably associated with chromatin.