Precise positioning of the histone-H3 variant, CENP-A, ensures centromere stability and faithful chromosomal segregation. Mislocalization of CENP-A to extra-centromeric loci results in aneuploidy and compromised cell viability associated with formation of ectopic kinetochores. The mechanism that retargets mislocalized CENP-A back to the centromere is unclarified. We show here that the downregulation of the histone H3 lysine 36 (H3K36) methyltransferase Set2 can preserve centromere localization of a temperature-sensitive mutant cnp1-1 Schizosaccharomyces pombe CENP-A (SpCENP-A) protein and reverse aneuploidy by redirecting mislocalized SpCENP-A back to centromere from ribosomal DNA (rDNA) loci, which serves as a sink for the delocalized SpCENP-A. Downregulation of set2 augments Swc2 (SWR1 complex DNA-binding module) expression and releases histone chaperone Ccp1 from the centromeric reservoir. Swc2 and Ccp1 are directed to the rDNA locus to excavate the SpCENP-Acnp1-1, which is relocalized to the centromere in a manner dependent on canonical SpCENP-A loaders, including Mis16, Mis17 and Mis18, thereby conferring cell survival and safeguarding chromosome segregation fidelity. Chromosome missegregation is a severe genetic instability event that compromises cell viability. This mechanism thus promotes CENP-A presence at the centromere to maintain genomic stability.

中文翻译：

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Set2 通过重定向 CENP-A 调节 Ccp1 和 Swc2 以确保着丝粒稳定性

组蛋白 H3 变体 CENP-A 的精确定位可确保着丝粒稳定性和忠实的染色体分离。CENP-A 错位到着丝粒外位点会导致非整倍性和与异位动粒形成相关的细胞活力受损。将错误定位的 CENP-A 重新定位回着丝粒的机制尚不清楚。我们在这里表明，组蛋白 H3 赖氨酸 36 (H3K36) 甲基转移酶 Set2 的下调可以保留温度敏感突变体 cnp1-1 粟酒裂殖酵母 CENP-A (SpCENP-A) 蛋白的着丝粒定位，并通过重定向错误定位的 SpCENP-A 来逆转非整倍性从核糖体 DNA (rDNA) 位点回到着丝粒，该位点充当离域 SpCENP-A 的接收器。set2 的下调会增强 Swc2（SWR1 复合物 DNA 结合模块）的表达，并从着丝粒库中释放组蛋白伴侣 Ccp1。Swc2 和 Ccp1 定向到 rDNA 基因座以挖掘 SpCENP-Acnp1-1，该 SpCENP-Acnp1-1 以依赖于经典 SpCENP-A 装载机（包括 Mis16、Mis17 和 Mis18）的方式重新定位到着丝粒，从而赋予细胞存活并保障染色体分离保真度。染色体错误分离是一种严重的遗传不稳定事件，会损害细胞活力。因此，这种机制促进着丝粒中 CENP-A 的存在，以维持基因组稳定性。