Assembly and epigenetic inheritance of the human centromere

染色体错误分离和非整倍体是肿瘤的常见特征。 着丝粒是确定动粒形成位点的染色体基因座， 确保在有丝分裂期间染色体的可靠分离。着丝粒同一性是 表观遗传学上通过CENP-A核小体的掺入来指定，独立于 DNA序列由于着丝粒的染色质性质， 控制CENP-A核小体组装和核小体稳定性是必不可少的， 着丝粒特化的维持。必须将新的CENP-A添加到着丝粒上 在每个细胞周期中以一致和忠实的方式维持着丝粒 染色质和着丝粒的同一性。新的CENP-A核小体被添加到 着丝粒在G1期间被CENP-A特异性伴侣HJURP，其被招募以 由Mis 18复合体组成。虽然与经典组蛋白H3不同，新CENP-A 在DNA复制过程中不沉积;然而，CENP-A核小体保留在 DNA复制过程中的着丝粒，以确保着丝粒的透射率 基因座CENP-A核小体稳定保留的机制， 染色质在DNA复制过程中被分解的问题将在本申请中解决。 着丝粒位于大多数个体的α-卫星DNA重复序列内; 然而，已经鉴定出几种新着丝粒， 在非着丝粒位点重新定位和发挥作用。该应用程序将解决以下问题： 非着丝粒位点获得着丝粒身份，以了解 染色质和基因组对着丝粒功能的贡献。

Chromosome missegregation and aneuploidy are commons characteristics of cancer. Centromeres are chromosomal loci that define the site of kinetochore formation and ensure faithful chromosome segregation during mitosis. Centromeric identity is epigenetically specified by the incorporation of CENP-A nucleosomes, independent of DNA sequence. Because of the chromatin nature of the centromere, the processes that govern CENP-A nucleosome assembly and nucleosome stability are essential to the maintenance of centromere specification. New CENP-A must be added to the centromere in a consistent and faithful manner during each cell cycle to maintain centromeric chromatin and centromere identity. New CENP-A nucleosomes are added to the centromere during G1 by the CENP-A specific chaperone HJURP, that is recruited to centromere by the Mis18 complex. Although unlike canonical histone H3, new CENP-A is not deposited during DNA replication; however, CENP-A nucleosomes are retained at the centromere during DNA replication to ensure the transmittance of the centromeric locus. The mechanism by which CENP-A nucleosomes are stably retained when chromatin is disassembled during DNA replication will be addressed in this application. Centromeres are located within the alpha-satellite DNA repeats in most individuals; however, several neocentromeres have been identified where centromere proteins relocate and function at non-centromeric sites. This application will address the ability of non-centromeric sites to acquire centromeric identity in order to understand the chromatin and genomic contributions to centromere function.