Ohkuni Kentaro, Au Wei-Chun, Kazi Amira Z, Balachandra Vinutha, Basrai Munira A
Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Nucleic Acids Res. 2025 Feb 8;53(4). doi: 10.1093/nar/gkaf083.
Mislocalization of overexpressed CENP-A (Cse4 in budding yeast) contributes to chromosomal instability (CIN) in yeasts, flies, and human cells. Overexpression of CENP-A is observed in many cancers and this correlates with poor prognosis. Here, we show that altered stoichiometry of histone H3 and expression of oncohistone mutation H3 E97K contributes to mislocalization of Cse4 and CIN. Oncohistone mutations in the globular domain of histone H3 such as H3 E97K occur in several cancers; however, their functional effects remain unexplored. We demonstrated that strains with reduced gene dosage of histone H3 (hht1Δ and hht2Δ) or oncohistone H3 E97K mutation exhibit enhanced Cse4-H4 interaction, an in vivo change in the conformational state of Cse4, and this contributes to mislocalization of Cse4. Oncohistone H3 E97K mutant protein was unstable and exhibited defects in interaction with histone H4. Notably, mislocalization of Cse4 and CIN phenotypes were observed in hht1Δ and oncohistone H3 E97K mutants expressing endogenous Cse4. In summary, our studies highlight the importance of histone H3 stoichiometry in preventing mislocalization of Cse4 for chromosomal stability and suggest that oncohistone H3 mutations may contribute to CIN in human cancers.
过表达的着丝粒蛋白A（芽殖酵母中的Cse4）定位错误会导致酵母、果蝇和人类细胞中的染色体不稳定（CIN）。在许多癌症中都观察到了着丝粒蛋白A的过表达，这与预后不良相关。在这里，我们表明组蛋白H3化学计量的改变和癌组蛋白突变H3 E97K的表达导致了Cse4的定位错误和CIN。组蛋白H3球状结构域中的癌组蛋白突变，如H3 E97K，在几种癌症中出现；然而，它们的功能作用仍未得到探索。我们证明，组蛋白H3基因剂量降低的菌株（hht1Δ和hht2Δ）或癌组蛋白H3 E97K突变体表现出增强的Cse4-H4相互作用，这是Cse4构象状态在体内的变化，并且这导致了Cse4的定位错误。癌组蛋白H3 E97K突变蛋白不稳定，并且在与组蛋白H4相互作用方面表现出缺陷。值得注意的是，在表达内源性Cse4的hht1Δ和癌组蛋白H3 E97K突变体中观察到了Cse4的定位错误和CIN表型。总之，我们的研究强调了组蛋白H3化学计量在防止Cse4定位错误以维持染色体稳定性方面的重要性，并表明癌组蛋白H3突变可能在人类癌症中导致CIN。
