OnlineFirst on October 12 , 2010 as 10 . 1158 / 0008 - 5472 . CAN - 10 - 0312 Cancer esearch or and Stem Cell Biology rnative Cyclin D 1 Splice Forms Differentially Regulate the R Damage Response

Downlo DNA damage response (DDR) activates downstream pathways including cell cycle checkpoints. The D1 gene is overexpressed or amplified in many human cancers and is required for gastrointestinal, , and skin tumors in murine models. A common polymorphism in the human cyclin D1 gene is atively spliced, resulting in cyclin D1a and D1b proteins that differ in their carboxyl terminus. Cyclin erexpression enhances DNA damage–induced apoptosis. The role of cyclin D1 and the alternative form in regulating the DDR is not well understood. Herein cyclin D1a overexpression enhanced the s characterized by induction of γH2AX phosphorylation, the assembly of DNA repair foci, specific tment of DNA repair factors to chromatin, and G2-M arrest. Cyclin D1 deletion in fibroblasts or interfering RNA–mediated reduction of endogenous cyclin D1 in colon cancer cells reduced the small 5-fluorouracil–mediated DDR. Mechanistic studies showed that cyclin D1a, like DNA repair factors, elicited the DDR when stably associated with chromatin. Cancer Res; 70(21); OF1–10. ©2010 AACR.