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The kinetochore (centromeric DNA and associated proteins) is a key determinant for high fidelity chromosome transmission. Evolutionarily conserved Scm3p is an essential component of centromeric chromatin and is required for assembly and function of kinetochores in humans, fission yeast, and budding yeast. Overexpression of  HJURP , the mammalian homolog of budding yeast Scm3p, has been observed in lung and breast cancers and is associated with poor prognosis; however, the physiological relevance of these observations is not well understood. We overexpressed  SCM3  and  HJURP  in  Saccharomyces cerevisiae  and  HJURP  in human cells and defined domains within Scm3p that mediate its chromosome loss phenotype. Our results showed that the overexpression of  SCM3  ( GALSCM3 ) or  HJURP  ( GALHJURP ) caused chromosome loss in a wild-type yeast strain, and overexpression of  HJURP  led to mitotic defects in human cells.  GALSCM3  resulted in reduced viability in kinetochore mutants, premature separation of sister chromatids, and reduction in Cse4p and histone H4 at centromeres. Overexpression of  CSE4  or histone H4 suppressed chromosome loss and restored levels of Cse4p at centromeres in  GALSCM3  strains. Using mutant alleles of  scm3 , we identified a domain in the N-terminus of Scm3p that mediates its interaction with  CEN  DNA and determined that the chromosome loss phenotype of  GALSCM3  is due to centromeric association of Scm3p devoid of Cse4p/H4. Furthermore, we determined that similar to other systems the centromeric association of Scm3p is cell cycle regulated. Our results show that altered stoichiometry of Scm3p/HJURP, Cse4p, and histone H4 lead to defects in chromosome segregation. We conclude that stringent regulation of  HJURP  and  SCM3  expression are critical for genome stability.

Misregulation of Scm3p/HJURP Causes Chromosome Instability in Saccharomyces cerevisiae and Human Cells