The mitotic fidelity gene (MIF-2) from Saccharomyces cerevisiae is required for maintaining the structural integrity of the mitotic spindle during anaphase spindle elongation. MIF-2 is noted for its ability to destabilize chromosome VII when it is overexpressed. Experimentally, the destabilization has been actualized as errors in chromosome segregation which exceeded wild-type error rates by 17-fold (Meeks-Wagner, D. and L. H. Hartwell (1986) Cell 48:43-52). Subsequently, the gene for MIF-2 has been cloned, mapped to yeast chromosome XI, and used in various transformation studies. Overexpression of MIF-2 suspended chromosome segregation, and the arrest of cell division produced large budded cells incapable of further growth. The gene for MIF-2 shares at least two regions of similarity with mammalian centromere protein (CENP-C), an integral component of active kinetochores.
Meluh and Koshland (GenBank g881372) first isolated the yeast gene SMT3 which suppresses MIF-2 mutations. SMT3, which is located on yeast chromosome IV, has homology to a human cDNA; the human mRNA transcripts were present in heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas. The deduced amino acid sequence of human SMT3 has 95 residues and .about.50% identity to the yeast amino acid sequence (Mannen, H. et al. (1996) Biochem. Biophys. Res. Commun. 222:178-180). The discovery of other SMT3 genes in various organisms suggests that these proteins constitute a gene family and have been evolutionarily conserved for their role in maintaining spindle/kinetochore function.
SMT3A is a human homolog located in the telomeric region of chromosome 21. The gene encodes a protein with approximately 40% homology to SMT3 genes of protozoa, yeast, Caenorhabditis, and rice. The predicted protein has 103 amino acids and shows 29% identity to ubiquitin-like proteins which are known to modify spindle functions and participate in DNA repair. Investigators have suggested that allelic dosage and expression of SMT3A may be important in preventing Down's syndrome and may also be involved in the manifestation of other genetic diseases the genes for which are located in the telomeric region of chromosome 21 (Lapenta, V. et al. (1977) Genomics 40:362-6). These diseases include myoclonus epilepsy, autoimmune polyglandular disease type 1, autosomal nonsyndromic deafness, holoprosencephaly, Knobloch syndrome, Bethlem myopathy and one form of bipolar affective disorder.
The discovery of a human SMT3-like protein and the polynucleotides encoding it satisfies a need in the art by providing a means for diagnosis, prevention, and treatment of disorders of cell division.