DNA Polymerases as Potential Therapeutic Targets for Cancers Deficient in the DNA Mismatch Repair Proteins MSH2 or MLH1

Sarah A. Martin, Nuala McCabe, Michelle Mullarkey, Robert Cummins, Darren J. Burgess, Yusaku Nakabeppu, Sugako Oka, Elaine Kay, Christopher J. Lord, Alan Ashworth

Research output: Contribution to journalArticle

135 Citations (Scopus)

Abstract

Synthetic sickness/lethality (SSL) can be exploited to develop therapeutic strategies for cancer. Deficiencies in the tumor suppressor proteins MLH1 and MSH2 have been implicated in cancer. Here we demonstrate that deficiency in MSH2 is SSL with inhibition of the DNA polymerase POLB, whereas deficiency in MLH1 is SSL with DNA polymerase POLG inhibition. Both SSLs led to the accumulation of 8-oxoG oxidative DNA lesions. MSH2/POLB SSL caused nuclear 8-oxoG accumulation, whereas MLH1/POLG SSL led to a rise in mitochondrial 8-oxoG levels. Both SSLs were rescued by silencing the adenine glycosylase MUTYH, suggesting that lethality could be caused by the formation of lethal DNA breaks upon 8-oxoG accumulation. These data suggest targeted, mechanism-based therapeutic approaches.

Original languageEnglish
Pages (from-to)235-248
Number of pages14
JournalCancer Cell
Volume17
Issue number3
DOIs
Publication statusPublished - Mar 16 2010

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cell Biology
  • Cancer Research

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    Martin, S. A., McCabe, N., Mullarkey, M., Cummins, R., Burgess, D. J., Nakabeppu, Y., Oka, S., Kay, E., Lord, C. J., & Ashworth, A. (2010). DNA Polymerases as Potential Therapeutic Targets for Cancers Deficient in the DNA Mismatch Repair Proteins MSH2 or MLH1. Cancer Cell, 17(3), 235-248. https://doi.org/10.1016/j.ccr.2009.12.046