DNA polymerases as potential therapeutic targets for DNA mismatch repair deficient cancers
Sarah Martin1, Nuala McCabe1, Michelle Mullarkey2, Robert Cummins2, Elaine Kay2, Christopher Lord1, Alan Ashworth1
1Institute of Cancer Research, London, UK, 2The Royal College of Surgeons in Ireland, Dublin, Ireland
Proffered paper presentation
Background
Base oxidation is one of the most common forms of DNA damage. Some lesions that are formed by this process, such as 8-Oxoguanine (8-oxoG), are repaired by the Base Excision Repair (BER) pathway. This pathway is instigated by the excision of the damaged base by the DNA glycosylase OGG1, followed by repair of the residual lesion by a number of enzymes that include DNA Polymerase b (POLB). Oxidative DNA damage can also be repaired by the Mismatch Repair (MMR) pathway, deficiency of which predisposes to a number of cancer types, including colorectal tumours.
Results
Using RNA interference screening, we demonstrate that deficiency in the MMR gene MSH2 is synthetically lethal with inhibition of POLB whereas deficiency of the MMR gene MLH1, is synthetically lethal with DNA polymerase g (POLG) inhibition. In both tumour cell lines and tumor biopsies, MSH2 and MLH1 deficiencies correlate with elevated expression of POLB or POLG respectively, suggesting potential functional compensation. The combination of deficiency in MSH2 and POLB results in accumulation of 8-oxoG lesions in nuclear DNA, whereas an increase in mitochondrial DNA 8-oxoG lesions characterise the MLH1/POLG interaction. POLB silencing reduces OGG1 expression, perhaps explaining the accumulation of nuclear 8-oxoG lesions and both MSH2/POLB and MLH1/POLG lethalities can be rescued by inhibition of the adenine glycosylase, MUTYH. This latter observation suggests that the formation of single strand DNA breaks that eventually stall and collapse replication forks could explain the MSH2/POLB and MLH1/POLG lethalities, a hypothesis supported by genotype-specific increases in gH2AX foci formation.
Conclusion
Given the well-established links between MLH1 and MSH2 deficiencies and cancer predisposition, these data suggest novel, mechanism-based therapeutic approaches.
