MDS1, A DOSAGE SUPPRESSOR OF AN MCK1 MUTANT, ENCODES A PUTATIVE YEASTHOMOLOG OF GLYCOGEN-SYNTHASE KINASE-3

The yeast gene MCK1 encodes a serine/threonine protein kinase that is thought to function in regulating kinetochore activity and entry into meiosis. Disruption of MCK1 confers a cold-sensitive phenotype, a temp erature-sensitive phenotype, and sensitivity to the microtubule-destab ilizing drug benomyl and leads to loss of chromosomes during growth on benomyl. A dosage suppression selection was used to identify genes th at, when present at high copy number, could suppress the cold-sensitiv e phenotype of mck1=HIS3 mutant cells. Several unique classes of clone s were identified, and one of these, designated MDS1, has been charact erized in some detail. Nucleotide sequence data reveal that MDS1 encod es a serine/threonine protein kinase that is highly homologous to the shaggy/zw3 kinase in Drosophila melanogaster and its functional homolo g, glycogen synthase kinase 3, in rats. The presence of MDS1 in high c opy number rescues both the cold-sensitive and the temperature-sensiti ve phenotypes, but not the benomyl-sensitive phenotype, associated wit h the disruption of MCK1. Analysis of strains harboring an mds1 null m utation demonstrates that MDS1 is not essential during normal vegetati ve growth but appears to be required for meiosis. Finally, in vitro ex periments indicate that the proteins encoded by both MCK1 and MDS1 pos sess protein kinase activity with substrate specificity similar to tha t of mammalian glycogen synthase kinase 3.