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.
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Acknowledgements
We would like to thank Dr RM Liskay for the immortalized MEF cell lines. We would also like to thank Dr HT Riele for the Msh2 deficient mice. This work was supported by the Cancer Research Campaign (UK). AR Clarke is supported by the Royal Society.
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Strathdee, G., Sansom, O., Sim, A. et al. A role for mismatch repair in control of DNA ploidy following DNA damage. Oncogene 20, 1923–1927 (2001). https://doi.org/10.1038/sj.onc.1204276
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DOI: https://doi.org/10.1038/sj.onc.1204276
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