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

Overview

Journal Cancer Cell

Publisher Cell Press

Specialty Oncology

Date 2010 Mar 16

PMID 20227038

Citations 85

Authors

Sarah A Martin

Nuala McCabe

Michelle Mullarkey

Robert Cummins

Darren J Burgess

Yusaku Nakabeppu

Sugako Oka

Elaine Kay

Christopher J Lord

Alan Ashworth

Affiliations

Soon will be listed here.

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.

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