Alternative cyclin D1 splice forms differentially regulate the DNA damage response

Zhiping Li, Xuanmao Jiao, Chenguang Wang, L. Andrew Shirley, Hany Elsaleh, Olav Dahl, Min Wang, Evi Soutoglou, Erik S. Knudsen, Richard G. Pestell

Research output: Contribution to journalArticle

90 Scopus citations

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 G2-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.

Original languageEnglish (US)
Pages (from-to)8802-8811
Number of pages10
JournalCancer research
Volume70
Issue number21
DOIs
StatePublished - Nov 1 2010

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Li, Z., Jiao, X., Wang, C., Shirley, L. A., Elsaleh, H., Dahl, O., Wang, M., Soutoglou, E., Knudsen, E. S., & Pestell, R. G. (2010). Alternative cyclin D1 splice forms differentially regulate the DNA damage response. Cancer research, 70(21), 8802-8811. https://doi.org/10.1158/0008-5472.CAN-10-0312