Correct localization of the centromeric histone variant CenH3/CENP-A/Cse4 is an important part of faithful chromosome segregation. Mislocalization of CenH3 could affect chromosome segregation, DNA replication and transcription. CENP-A is often overexpressed and mislocalized in cancer genomes, but the underlying mechanisms are not understood. One major regulator of Cse4 deposition is Psh1, an E3 ubiquitin ligase that controls levels of Cse4 to prevent deposition into non-centromeric regions. We present evidence that Chromatin assembly factor-1 (CAF-1), an evolutionarily conserved histone H3/H4 chaperone with subunits shown previously to interact with CenH3 in flies and human cells, regulates Cse4 deposition in budding yeast. yCAF-1 interacts with Cse4 and can assemble Cse4 nucleosomes in vitro. Loss of yCAF-1 dramatically reduces the amount of Cse4 deposited into chromatin genome-wide when Cse4 is overexpressed. The incorporation of Cse4 genome-wide may have multifactorial effects on growth and gene expression. Loss of yCAF-1 can rescue growth defects and some changes in gene expression associated with Cse4 deposition that occur in the absence of Psh1-mediated proteolysis. Incorporation of Cse4 into promoter nucleosomes at transcriptionally active genes depends on yCAF-1. Overall our findings suggest CAF-1 can act as a CenH3 chaperone, regulating levels and incorporation of CenH3 in chromatin.

中文翻译：

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染色质组装因子-1（CAF-1）伴侣分子调节Cse4在发芽酵母中沉积到染色质中

着丝粒组蛋白变体CenH3 / CENP-A / Cse4的正确定位是忠实染色体分离的重要组成部分。CenH3的错误定位可能会影响染色体分离，DNA复制和转录。CENP-A通常在癌症基因组中过表达和定位错误，但尚不清楚其潜在机制。Cse4沉积的主要调节剂是Psh1，它是一种E3泛素连接酶，可控制Cse4的水平以防止沉积到非着丝粒区域中。我们目前的证据表明，染色质组装因子1（CAF-1），一种进化上保守的组蛋白H3 / H4分子伴侣，其亚基先前显示与果蝇和人类细胞中的CenH3相互作用，调节Cse4在发芽酵母中的沉积。yCAF-1与Cse4相互作用并可以在体外组装Cse4核小体。当Cse4过表达时，yCAF-1的丢失会大大减少沉积在整个染色质基因组中的Cse4的数量。在整个基因组中掺入Cse4可能会对生长和基因表达产生多方面的影响。yCAF-1的丢失可以挽救生长缺陷，以及在缺乏Psh1介导的蛋白水解作用下发生的与Cse4沉积相关的基因表达的某些变化。将Cse4整合到转录活性基因的启动子核小体上取决于yCAF-1。总体而言，我们的发现表明CAF-1可以充当CenH3伴侣，调节染色质中CenH3的水平和掺入。