Regulation of kinetochore function in yeast by modification of the core region of the centromeric nucleosome
Final Report Abstract
Centromeres are the chromosomal regions where kinetochores assemble, forming a physical bridge between DNA and microtubules. During mitosis and meiosis, microtubules pull chromosomes apart, ensuring their accurate segregation to the daughter cells. Errors in this process can result in aneuploidy, contributing to diseases such as cancer and infertility. In this project, we used the yeast centromere as a model to uncover novel mechanisms of centromere regulation. We identified and characterized protein modifications on centromeric proteins that influence the stability of the centromeric nucleosome. We found that these defects in nucleosome stability can be alleviated by strengthening interactions among outer kinetochore proteins, revealing an unexpected functional link between centromeric chromatin and microtubule-proximal kinetochore components. Additionally, we discovered an unexpected mode of centromere regulation involving sugar moieties that may be covalently attached to centromeric proteins. This finding suggests a potential mechanism by which the cell's nutritional state may influence cell cycle progression and chromosome segregation. Finally, we identified a new role for the histone chaperone Yta7 in regulating levels of the centromerespecific histone variant. Our results suggest that Yta7 functions as a hexameric ring that unfolds the histone variant and delivers it to a dedicated deposition machinery for incorporation into centromeric chromatin. This mechanism provides insight into the function of the human homolog ATAD2, which is frequently overexpressed in cancer.
Publications
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The ATAD2/ANCCA homolog Yta7 cooperates with Scm3 HJURP to deposit Cse4 CENP-A at the centromere in yeast. Proceedings of the National Academy of Sciences, 117(10), 5386-5393.
Shahnejat-Bushehri, Sara & Ehrenhofer-Murray, Ann E.
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A role for β-1,6- and β-1,3-glucans in kinetochore function in Saccharomyces cerevisiae. GENETICS, 226(2).
Kshirsagar, Rucha; Munhoven, Arno; Tran Nguyen, Tra My & Ehrenhofer-Murray, Ann E.
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Methylation of CENP-A/Cse4 on arginine 143 and lysine 131 regulates kinetochore stability in yeast. GENETICS, 223(4).
Tran Nguyen, Tra My; Munhoven, Arno; Samel-Pommerencke, Anke; Kshirsagar, Rucha; Cuomo, Alessandro; Bonaldi, Tiziana & Ehrenhofer-Murray, Ann E.
