Defective DNA Mismatch Repair-dependent c-Abl-p73-GADD45α Expression Confers Cancer Chemoresistance

This chapter discusses the defective DNA mismatch repair (MRR). DNA mismatch repair (MMR) is a highly conserved repair pathway that plays an important role in the detection and correction of errors created during/after DNA replication (i.e., post-replication repair) and/or after natural genetic recombination events. Genes encoding homologs of bacterial MutS and MutL have been identified in a variety of eukaryotic model systems, including yeast, plants, insects, nematodes, and mammals. In contrast, MMR-deficient cells ignore these DNA lesions, leading to chemoresistance and damage tolerance to O6-meG DNA lesions generated by specific alkylating agents, such as Temozolomide (TMZ). The net effect is the emergence of drug-resistant, highly mutagenic cell populations that progress rapidly to kill the patient. Potential strategies to overcome MMR-deficient mediated chemoresistance based on accumulated evidence were discussed and included the use of agents, such as FdCyd, that can simultaneously hypomethylate an epigenetically silenced hMLH1 promoter resulting in hMLH1 re-expression, and sensitize the emerging cells that have restored MMR capacity.