Misregulation of Scm3p/HJURP causes chromosome instability in Saccharomyces cerevisiae and human cells.
Misregulation of Scm3p/HJURP causes chromosome instability in Saccharomyces cerevisiae and human cells.
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DOI：
10.1371/journal.pgen.1002303
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发表时间：
2011-09
期刊：
影响因子：
4.5
通讯作者：
Basrai MA
中科院分区：
文献类型：
--
作者：
Mishra PK;Au WC;Choy JS;Kuich PH;Baker RE;Foltz DR;Basrai MA
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. Proper chromosome segregation is essential for normal cell proliferation. Segregation errors lead to aneuploidy, a direct cause of birth defects and a hallmark of cancer. The kinetochore (centromeric DNA and associated proteins) is one of the key determinants for faithful chromosome transmission. Misregulation of kinetochore proteins such as HJURP has been observed in various cancers, however the biological relevance of this observation is not well understood. We determined that altered dosage of HJURP and its budding yeast homolog SCM3 leads to defects in chromosome segregation in yeast and human cells. We identified the centromeric DNA–interacting domain of Scm3p and determined that association of Scm3p devoid of Cse4p leads to chromosome segregation defects. Our findings suggest that stringent regulation of Scm3p/HJURP, Cse4p, and histone H4 is critical for maintenance of genome stability.
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