Aurora B/AIR-2调控姐妹染色单体中心点分辨率及CENP-A/HCP-3组织，防止多向连接
Aurora B/AIR-2 regulates sister centromere resolution and CENP-A/HCP-3 organization to prevent merotelic attachments
影响因子:5.90000
分区:生物学2区 / 细胞生物学3区
发表日期:2025 May 02
作者:
Yue Wang, Charmaine Yan Yu Wong, Karen Wing Yee Yuen
摘要
在细胞分裂过程中，正确捕获在染色体着丝粒上的姐妹微管组织的运动，决定了染色体的正确分离。为了确保姐妹染色单体的正确分离，姐妹中心点必须先进行分辨以实现双极定向，然后再进行微管连接。中心点未能正确分辨会增加多向连接（merotelic attachments）的发生率，即来自相反极的微管同时连接到同一姐妹着丝点，导致染色体滞后、非整倍体，甚至癌症进展。关于Aurora B介导的应变感知机制以纠正错误的着丝点-微管连接已被广泛研究，但在早期有丝分裂阶段预防多向连接的机制尚不清楚。本研究发现，抑制有丝分裂激酶Aurora B／AIR-2会增加线虫（C. elegans）中的多向连接。一方面，Aurora B/AIR-2缺失细胞表现出中心点分辨的延迟及染色质中凝缩素II组分定位的紊乱；另一方面，缺失Aurora B/AIR-2会导致着丝点蛋白CENP-A/HCP-3和M18BP1/KNL-2以及着丝粒蛋白MIS-12在染色质上的异常积累，可能形成异位着丝点，诱发错误连接。综上所述，本研究阐明Aurora B／AIR-2调控姐妹中心点分辨及CENP-A/HCP-3沉积，主动预防多向连接及染色体不稳定。
Abstract
During cell division, the accurate capture of sister kinetochores that are built on the centromeres of chromosomes by microtubules emanating from opposite spindle poles governs faithful chromosome segregation. To ensure sister chromatids separate correctly, sister centromeres undergo resolution to achieve bipolar orientation prior to microtubule attachments. Failure of centromere resolution increases the frequency of merotelic attachments, with microtubules from opposite poles attaching to the same sister kinetochore, causing lagging chromosome, aneuploidy, and even cancer progression. The Aurora B-mediated tension-sensing machinery to correct erroneous kinetochore-microtubule attachments has been well studied. However, preventative mechanisms to avoid merotelic attachments that occur in the earlier mitotic stage are poorly understood. In this study, we found that inactivation of mitotic kinase Aurora B/AIR-2 increases merotelic attachments in Caenorhabditis elegans. On one hand, Aurora B/AIR-2-deficient cells exhibit a delay in the occurrence of centromere resolution and a disruption in targeting condensin II components to chromatin. On the other hand, loss of Aurora B/AIR-2 results in an increased localization of centromeric proteins CENP-A/HCP-3 and M18BP1/KNL-2 as well as the kinetochore protein MIS-12 on chromatin, which may generate ectopic kinetochores causing erroneous attachments. To conclude, this study elucidated that Aurora B/AIR-2 regulates sister centromere resolution and CENP-A/HCP-3 deposition to actively prevent merotely and chromosome instability in cells.