Aurora B/AIR-2调节姐妹染色体中心的解析与CENP-A/HCP-3的组织，以防止merotelic连接

Aurora B/AIR-2 regulates sister centromere resolution and CENP-A/HCP-3 organization to prevent merotelic attachments

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Journal of Molecular Cell Biology

影响因子:5.9

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

DOI: 10.1093/jmcb/mjae045

摘要

在细胞分裂过程中，来自相反纺锤体极的微管正确捕获建立在染色体着丝粒上的姐妹动粒，决定了正确的染色体分离。为了确保姐妹染色单体正确分离，姐妹着丝粒必须经历解析以实现双极定向，然后才发生微管的结合。未能完成着丝粒解析会增加merotelic连接的发生率，即来自相反极的微管同时连接到同一姐妹动粒，导致染色体滞留、非整倍体甚至癌症进展。关于Aurora B介导的张力感应机制以校正错误的动粒-微管连接已被广泛研究。然而，用以预防早期有丝分裂阶段发生的merotelic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会增加线虫中的merotelic连接。一方面，缺失Aurora B/AIR-2的细胞在着丝粒解析的发生上表现出延迟，并且在染色质上目标定位凝聚素II组分受到干扰。另一方面，缺失Aurora B/AIR-2会导致着丝粒蛋白CENP-A/HCP-3和M18BP1/KNL-2以及动粒蛋白MIS-12在染色质上的积聚增加，这可能形成异位动粒，导致错误的连接。总之，本研究阐明Aurora B/AIR-2调控姐妹着丝粒的解析和CENP-A/HCP-3的沉积，以积极防止merotely和细胞染色体不稳定。

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.