THE PRODUCTS OF THE YEAST MMS2 AND 2 HUMAN HOMOLOGS (HMMS2 AND CROC-1) DEFINE A STRUCTURALLY AND FUNCTIONALLY CONSERVED UBC-LIKE PROTEIN FAMILY

Eukaryotic genes encoding ubiquitin-congugating enzyme (Ubc)-like prot eins have been isolated from both human and yeast cells. The CROC-1 ge ne was isolated by its ability to transactivate c-fos expression in ce ll culture through a tandem repeat enhancer sequence. The yeast MMS2 g ene was cloned by its ability to complement the methyl methanesulfonat e sensitivity of the mms2-1 mutant and was later shown to be involved in DNA post-replication repair. We report here the identification of a human MMS2 (hMMS2) cDNA encoding a novel human Ubc-like protein. hMMS 2 and CROC-1 share >90% amino acid sequence identity, but their DNA pr obes hybridize to distinct transcripts. hMMS2 and CROC-1 also share si milar to 50% identity and 75% similarity with the entire length of yea st Mms2, Unlike CROC-1, whose transcript appears to be elevated in all tumor cell lines examined, the hMMS2 transcript is only elevated in s ome tumor cell lines. Collectively, these results indicate that eukary otic cells may contain a highly conserved family of Ubc-like proteins that play roles in diverse cellular processes, ranging from DNA repair to signal transduction and cell differentiation. The hMMS2 and CROC-1 genes are able to functionally complement the yeast mms2 defects with regard to sensitivity to DNA damaging agents and spontaneous mutagene sis. Conversely, both MMS2 and hMMS2 were able to transactivate a c-fo s-CAT reporter gene in Rat-1 cells in a transient co-transfection assa y. We propose that either these proteins function in a common cellular process, such as DNA repair, or they exert their diverse biological r oles through a similar biochemical interaction relative to ubiquitinat ion.