A HUMAN HOMOLOG OF THE SACCHAROMYCES-CEREVISIAE REV3 GENE, WHICH ENCODES THE CATALYTIC SUBUNIT OF DNA-POLYMERASE-ZETA

To get a better understanding of mutagenic mechanisms in humans, we ha ve cloned and sequenced the human homolog of the Saccharomyces cerevis iae REV3 gene. The yeast gene encodes the catalytic subunit of DNA pol ymerase zeta, a nonessential enzyme that is thought to carry out trans lesion replication and is responsible for virtually all DNA damage-ind uced mutagenesis and the majority of spontaneous mutagenesis. The huma n gene encodes an expected protein of 3,130 residues, about twice the size of the yeast protein (1,504 aa). The two proteins are 29% identic al in an aminoterminal region of approximate to 340 residues, 39% iden tical in a carboxyl-terminal region of approximate to 850 residues, an d 29% identical in a 55-residue region in the middle of the two genes. The sequence of the expected protein strongly predicts that it is the catalytic subunit of a DNA polymerase of the pot zeta type; the carbo xyl-terminal domain possesses, in the right order, the six motifs char acteristic of eukaryotic DNA polymerases, most closely resembles yeast pol zeta among all polymerases in the GenBank database, and Is differ ent from the human alpha, delta, and epsilon enzymes. Human cells expr essing high levels of an hsREV3 antisense RNA fragment grow normally, but show little or no UV-induced mutagenesis and are slightly more sen sitive to killing by UV. The human gene therefore appears to carry out a function similar to that of its yeast counterpart.