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

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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

Fingerprint

Cyclin D1
DNA Damage
Cyclins
bcl-1 Genes
DNA Repair
Chromatin
Cell Cycle Checkpoints
Fluorouracil
Colonic Neoplasms
Small Interfering RNA
Fibroblasts
Phosphorylation
Apoptosis
Breast Neoplasms
Skin
Neoplasms
Proteins

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Li, Z., Jiao, X., Wang, C., Shirley, L. A., Elsaleh, H., Dahl, O., ... 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

Alternative cyclin D1 splice forms differentially regulate the DNA damage response. / Li, Zhiping; Jiao, Xuanmao; Wang, Chenguang; Shirley, L. Andrew; Elsaleh, Hany; Dahl, Olav; Wang, Min; Soutoglou, Evi; Knudsen, Erik S.; Pestell, Richard G.

In: Cancer Research, Vol. 70, No. 21, 01.11.2010, p. 8802-8811.

Research output: Contribution to journalArticle

Li, Z, Jiao, X, Wang, C, Shirley, LA, Elsaleh, H, Dahl, O, Wang, M, Soutoglou, E, Knudsen, ES & Pestell, RG 2010, 'Alternative cyclin D1 splice forms differentially regulate the DNA damage response', Cancer Research, vol. 70, no. 21, pp. 8802-8811. https://doi.org/10.1158/0008-5472.CAN-10-0312
Li, Zhiping ; Jiao, Xuanmao ; Wang, Chenguang ; Shirley, L. Andrew ; Elsaleh, Hany ; Dahl, Olav ; Wang, Min ; Soutoglou, Evi ; Knudsen, Erik S. ; Pestell, Richard G. / Alternative cyclin D1 splice forms differentially regulate the DNA damage response. In: Cancer Research. 2010 ; Vol. 70, No. 21. pp. 8802-8811.
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