Ludwig Institute for Cancer Research and Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA, USA.
Department of Pharmacology & Chemical Biology, School of Medicine, University of Pittsburgh Cancer Institute (UPCI), University of Pittsburgh, Pittsburgh, PA, USA.
Nat Cell Biol. 2019 Jun;21(6):743-754. doi: 10.1038/s41556-019-0331-4. Epub 2019 Jun 3.
Chromatin assembled with the histone H3 variant CENP-A is the heritable epigenetic determinant of human centromere identity. Using genome-wide mapping and reference models for 23 human centromeres, CENP-A binding sites are identified within the megabase-long, repetitive α-satellite DNAs at each centromere. CENP-A is shown in early G1 to be assembled into nucleosomes within each centromere and onto 11,390 transcriptionally active sites on the chromosome arms. DNA replication is demonstrated to remove ectopically loaded, non-centromeric CENP-A. In contrast, tethering of centromeric CENP-A to the sites of DNA replication through the constitutive centromere associated network (CCAN) is shown to enable precise reloading of centromere-bound CENP-A onto the same DNA sequences as in its initial prereplication loading. Thus, DNA replication acts as an error correction mechanism for maintaining centromere identity through its removal of non-centromeric CENP-A coupled with CCAN-mediated retention and precise reloading of centromeric CENP-A.
用组蛋白 H3 变体 CENP-A 组装的染色质是人类着丝粒身份的可遗传表观遗传决定因素。通过对 23 个人类着丝粒的全基因组作图和参考模型，在每个着丝粒的兆碱基长重复α-卫星 DNA 内鉴定出 CENP-A 结合位点。在早期 G1 中，CENP-A 被组装到每个着丝粒内的核小体中，并组装到染色体臂上的 11390 个转录活性位点上。已经证明 DNA 复制可以去除异位加载的非着丝粒 CENP-A。相比之下，通过组成型着丝粒相关网络 (CCAN) 将着丝粒 CENP-A 固定在 DNA 复制位点上，被证明可以使着丝粒结合的 CENP-A 精确地重新加载到与初始复制前加载相同的 DNA 序列上。因此，DNA 复制通过去除非着丝粒 CENP-A 并通过 CCAN 介导的保留和精确重新加载着丝粒 CENP-A 来作为维持着丝粒身份的纠错机制。
