Family A and B DNA Polymerases in Cancer: Opportunities for Therapeutic Interventions

Abstract

DNA polymerases are essential for genome replication, DNA repair and translesion DNA synthesis (TLS). Broadly, these enzymes belong to two groups: replicative and non-replicative DNA polymerases. A considerable body of data suggests that both groups of DNA polymerases are associated with cancer. Many mutations in cancer cells are either the result of error-prone DNA synthesis by non-replicative polymerases, or the inability of replicative DNA polymerases to proofread mismatched nucleotides due to mutations in 3'-5' exonuclease activity. Moreover, non-replicative, TLS-capable DNA polymerases can negatively impact cancer treatment by synthesizing DNA past lesions generated from treatments such as cisplatin, oxaliplatin, etoposide, bleomycin, and radiotherapy. Hence, the inhibition of DNA polymerases in tumor cells has the potential to enhance treatment outcomes. Here, we review the association of DNA polymerases in cancer from the A and B families, which participate in lesion bypass, and conduct gene replication. We also discuss possible therapeutic interventions that could be used to maneuver the role of these enzymes in tumorigenesis.

Keywords: 3′-5′ exonuclease; DNA polymerase; DNA polymerase and cancer; base excision repair; cancer; mismatch repair; replication fork; therapy for mismatch repair deficient cancers; translesion DNA synthesis.

Figure 1

Structures of family A DNA polymerases. (A) superposition of the ternary complex crystal structures of polymerase θ [63] (green, tetrahydrofuran-ddATP; cyan, dTMP-ddATP) and the ternary complex of KlenTaq (magenta, Protein Data Bank file 1QSY, Li et al., [83]); (B) This figure shows three different conformations of O-helix. Depending upon the template, polymerase θ assumes different O-helix conformation to conduct translesion synthesis; (C) close-up of the active site in three crystal structures. Only metal B, which is Ca²⁺ (shown as green ball) was seen in the crystal structures of polymerase θ. Metal A (pink ball) as seen in the crystal structure of KlenTaq is also shown here. The three active site residues of KlenTaq (D610, D785 and E786) are also shown in this figure. For simplicity, the residues positions of only KlenTaq are marked.