Synthetic lethality as a therapeutic strategy for the treatment of MMR-deficient cancers. (A) DNA mismatch repair is a stepwise process. In the schematic the MutSα heterodimer (Msh2-Msh6) recognizes a single-base mispair while MutSβ (Msh2-Msh3) primarily (but not exclusively -) initiates the repair of larger insertions/deletions (IDLs) of two to four bases. Recognition activates the recruitment of MutLα (Mlh1-Pms2) and multiple downstream factors (for example, Exo1, PCNA, RFC, RPA, and DNA pol δ) for repair by lesion excision and strand resynthesis. Each MutS also has roles independent of these downstream effectors of MMR: as an example, MutSα associates with cell cycle regulators at sites of DNA damage to mediate arrest and apoptosis , while MutSβ contributes to the repair of double-strand breaks via recombinatorial single-strand annealing ,. Mutations in many factors from this pathway are associated with cancer. (B) Loss of A (for example, MSH2) is a common initiating event in many colorectal cancers. Candidate screening seeks to identify and exploit negative genetic relationships (synthetic sick/lethal) to selectively kill cells that harbor the MSH2 deficiency, but spare those lacking this cancer-related alteration.