DNA polymerase zeta and the control of DNA damage induced mutagenesis in eukaryotes

DNA damage induced mutations arising during the course of translesion replication are likely to be an important contributory cause in the development of many cancers. In budding yeast, Saccharomyces cerevisiae, a good model system with which to investigate this process, mutagenesis is associated with the RAD6 repair pathway and depends on the functions of the REV1, REV3 and REV7 genes. The Rev3 and Rev7 proteins are subunits of a new type of DNA polymerase, called DNA polymerase zeta, that appears to carry out translesion replication, but no other repair, recombination or replication function. Pol zeta replicates past a T-T cyclobutane dimer with a higher efficiency than yeast pol alpha, is less prone than this enzyme to insert an incorrect nucleotide and is more efficient at elongating from a mismatched terminus. Rev1 protein is a terminal nucleotidyl transferase that inserts dCMP opposite template G, A and abasic sites. Types of mutations induced during translesion replication appear to depend largely on lesion structure, but the frequency and accuracy of bypass also depend on replication conditions. Inhibition of the activity or expression of pol zeta may be clinically useful for patients undergoing cancer therapy or for those with a familial predisposition to cancer.