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A role for mismatch repair in control of DNA ploidy following DNA damage

Strathdee, Gordon, Sansom, Owen J., Sim, Alyson, Clarke, Alan Richard and Brown, Robert 2001. A role for mismatch repair in control of DNA ploidy following DNA damage. Oncogene 20 (15) , pp. 1923-1927. 10.1038/sj.onc.1204276

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Abstract

Many reports have shown a link between mismatch repair (MMR) deficiency and loss of normal cell cycle control, particularly loss of G2 arrest. However almost all of these studies utilized transformed cell lines, and thus the involvement of other genes in this phenotype cannot be excluded. We have examined the effects of cisplatin treatment on primary embryo fibroblasts (MEFs) derived from mice in which the MMR gene Msh2 had been inactivated (Msh2-/-). This analysis determined that both primary Msh2-/- and wild type (WT) fibroblasts exhibited an essentially identical G2 arrest following cisplatin treatment. Similarly, we observed a cisplatin-induced G2 arrest in immortalized MMR deficient (Mlh1-/- and Pms2-/-) and WT MEFs. p53 deficient primary MEFs (p53-/-) exhibited both a clear G2 arrest and an increase in cells with a DNA content of 8N in response to cisplatin. When the Msh2 and p53 defects were combined (p53-/-/Msh2-/-) the G2 arrest was essentially identical to the p53-/- fibroblasts. However, the p53-/-/Msh2-/- fibroblasts demonstrated a further increase in cells with an 8N DNA content, above that seen in the p53-/- fibroblasts. These results suggest that loss of MMR on its own is not enough to overcome G2 arrest following exposure to cisplatin but does play a role in preventing polyploidization, or aberrant DNA reduplication, in the absence of functional p53.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
European Cancer Stem Cell Research Institute (ECSCRI)
Subjects: Q Science > Q Science (General)
Q Science > QH Natural history > QH426 Genetics
Uncontrolled Keywords: Mismatch repair; cell cycle; polyploidy; p53; DNA damage.
Publisher: Nature Publishing
ISSN: 0950-9232
Last Modified: 18 Jan 2018 21:07
URI: http://orca-mwe.cf.ac.uk/id/eprint/61378

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