DNA polymerases and cancer

Key Points Fifteen DNA polymerases are encoded in mammalian genomes. Some function in the replication of the genome, but most participate in specialized DNA repair and DNA damage tolerance processes. The activity of these DNA polymerases will affect the response of a cell to DNA-damaging carcinogens and chemotherapeutic agents. Some DNA polymerases catalyse DNA synthesis on damaged sites in DNA, helping cells tolerate DNA damage by translesion DNA synthesis (TLS). TLS polymerases are specialized for the bypass of different DNA adducts. Defects in Pol η (also known as POLH) are responsible for the variant type of xeroderma pigmentosum (XP-V). Pol ζ (the catalytic subunit of which is REV3L) and REV1 are required for nearly all damage-induced base change mutagenesis in mammalian cells. Reduction of their activities sensitizes cells, including tumour cells, to DNA-damaging agents. However, chromosome rearrangements and inflammation can increase in the absence of these proteins, promoting carcinogenesis. The expression of some genes encoding DNA polymerases may be altered in some cancers. In breast cancers, levels of POLQ (which encodes Pol θ) seem to be the most elevated compared with normal levels of expression. Comprehensive studies of DNA polymerase protein levels in cancer remain to be carried out. The inhibition of DNA polymerase activities could be useful as an adjuvant to DNA-damaging therapies, and inhibitors for some polymerases have been found. Pharmacologically effective inhibitors highly specific for a single DNA polymerase remain to be identified. Whole-genome analyses of cancers have not yet revealed cancer-associated alterations in DNA polymerase genes. It seems likely, however, that at least some cells in a tumour will have relevant alterations. Some DNA polymerases can be considered as tumour suppressors (Pol ζ, REV1, Pol η, Pol ι, Pol κ, Pol δ and Pol ɛ). DNA polymerases have various roles from DNA replication to tolerating DNA damage through a process known as translesion DNA synthesis. This Review discusses the function of the DNA polymerase family and their possible roles in cancer. There are 15 different DNA polymerases encoded in mammalian genomes, which are specialized for replication, repair or the tolerance of DNA damage. New evidence is emerging for lesion-specific and tissue-specific functions of DNA polymerases. Many point mutations that occur in cancer cells arise from the error-generating activities of DNA polymerases. However, t