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Alternative cyclin D1 splice forms differentially regulate the DNA damage response.

Authors
  • Li, Zhiping
  • Jiao, Xuanmao
  • Wang, Chenguang
  • Shirley, L Andrew
  • Elsaleh, Hany
  • Dahl, Olav
  • Wang, Min
  • Soutoglou, Evi
  • Knudsen, Erik S
  • Pestell, Richard G
Type
Published Article
Journal
Cancer Research
Publisher
American Association for Cancer Research
Publication Date
Nov 01, 2010
Volume
70
Issue
21
Pages
8802–8811
Identifiers
DOI: 10.1158/0008-5472.CAN-10-0312
PMID: 20940395
Source
Medline
License
Unknown

Abstract

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, specific recruitment of DNA repair factors to chromatin, and G(2)-M arrest. Cyclin D1 deletion in fibroblasts or small interfering RNA-mediated reduction of endogenous cyclin D1 in colon cancer cells reduced the 5-fluorouracil-mediated DDR. Mechanistic studies showed that cyclin D1a, like DNA repair factors, elicited the DDR when stably associated with chromatin.

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