Inhibition of mutagenic translesion synthesis: A possible strategy for improving chemotherapy?

DNA damaging chemotherapy is the first line of treatment for certain cancers, but its long-term success is often marred by the eventual acquisition of chemoresistance. Other cancers cannot be treated because they are intrinsically resistant to such chemotherapy. These 2 types of resistance are coupled in the context of translesion synthesis (TLS), which is carried out by specialized TLS DNA polymerases that can replicate past DNA lesions but in a lower fidelity manner. First, TLS DNA polymerases permit the bypass of modified DNA bases during DNA synthesis, thereby allowing proliferation to continue in the presence of chemotherapy, an issue of particular relevance to intrinsic drug resistance. Second, mistakes introduced by TLS polymerases copying over DNA lesions introduced during the chemotherapy lead to mutations that contribute to acquired resistance. These dual functions of mutagenic TLS polymerases with respect to chemoresistance make these proteins very promising targets for adjuvant therapy. The major branch of mutagenic TLS requires REV1, a Y family DNA polymerase that recruits other TLS polymerases with its C-terminal domain (CTD) including POL zeta, which is also required. Recent evidence obtained using mouse models is summarized, which shows that interfering with REV1/POL zeta-dependent mutagenic TLS during DNA damaging chemotherapy can help overcome problems due to both intrinsic resistance and acquired resistance. Ways to develop drugs that block mutagenic TLS are also considered, including taking advantage of structural knowledge to target key protein-protein interfaces.