Chromatin Structure and Epigenetics Mechanisms Unit, Center for Cancer Research, National Cancer Institute National Institutes of Health, Bethesda, MD, United States of America.
PLoS One. 2018 Oct 26;13(10):e0205948. doi: 10.1371/journal.pone.0205948. eCollection 2018.
The centromere specific histone H3 variant CENP-A/CENH3 specifies where the kinetochore is formed in most eukaryotes. Despite tight regulation of CENP-A levels in normal cells, overexpression of CENP-A is a feature shared by various types of solid tumors and results in its mislocalization to non-centromeric DNA. How CENP-A is assembled ectopically and the consequences of this mislocalization remain topics of high interest. Here, we report that in human colon cancer cells, the H3.3 chaperones HIRA and DAXX promote ectopic CENP-A deposition. Moreover, the correct balance between levels of the centromeric chaperone HJURP and CENP-A is essential to preclude ectopic assembly by H3.3 chaperones. In addition, we find that ectopic localization can recruit kinetochore components, and correlates with mitotic defects and DNA damage in G1 phase. Finally, CENP-A occupancy at the 8q24 locus is also correlated with amplification and overexpression of the MYC gene within that locus. Overall, these data provide insights into the causes and consequences of histone variant mislocalization in human cancer cells.
着丝粒特异性组蛋白 H3 变体 CENP-A/CENH3 决定了大多数真核生物中动粒的形成位置。尽管在正常细胞中 CENP-A 的水平受到严格调控，但CENP-A 的过表达是各种实体瘤的共同特征，导致其错误定位到非着丝粒 DNA 上。CENP-A 如何异位组装以及这种错误定位的后果仍然是人们关注的热点。在这里，我们报告在人结肠癌细胞中，H3.3 伴侣蛋白 HIRA 和 DAXX 促进了异位 CENP-A 的沉积。此外，着丝粒伴侣蛋白 HJURP 和 CENP-A 之间的正确平衡对于防止 H3.3 伴侣蛋白的异位组装至关重要。此外，我们发现异位定位可以募集动粒成分，并与 G1 期的有丝分裂缺陷和 DNA 损伤相关。最后，8q24 基因座上的 CENP-A 占据也与该基因座内 MYC 基因的扩增和过表达相关。总的来说，这些数据为了解人类癌细胞中组蛋白变体错误定位的原因和后果提供了线索。
