ABSTRACT
Synthetic lethal interactions have been proposed to exist between mismatch repair (MMR) proteins and DNA repair polymerases, suggesting another useful approach in cancer treatment (Hartwell et al. 1997; Martin et al. 2010, 2011). Germline mutations in the MSH2 and MLH1 MMR genes are associated with hereditary nonpolyposis colorectal carcinomas (Jacob and Praz 2002), and sporadic colorectal cancer (Bettstetter et al. 2007). MMR corrects mispaired nucleotides, which can arise during replication or recombination, and also contributes to the repair of oxidative DNA damage (see Chapter 7). The DNA repair polymerases Pol β and Pol γ are involved in nuclear and mitochondrial base excision repair, respectively, a pathway that corrects oxidative damage to bases or nucleotides (see Chapter 8). Martin and colleagues reported that depletion of Pol β in MSH2 mutated cells and depletion of Pol γ in MLH1 mutated cells caused increased oxidative DNA damage and reduced clonogenic survival (Martin et al. 2010). Interestingly, Pol β and Pol γ expression levels were found to be elevated in MSH2 and MLH1 cells, respectively (Martin et al. 2010). In another report, Martin and colleagues also showed that PTEN-induced putative kinase 1 (PINK1) and other mitochondrial kinases had similar synthetic lethal relationships with MLH1 and MSH2 using high throughput RNA interference screens (Martin et al. 2011). These authors propose that these relationships exist due to an inability to repair oxidative DNA damage when the polymerases or kinases are depleted in MMR-defi cient cells (Martin et al. 2010, 2011). Such results suggest that inhibitors targeting Pol β or Pol γ could be useful in treating cancers with defects in MSH2 or MLH1.
