Zhao Lei, Yuan Xueying, Chen Qinfu, Yan Haiyan, Wang Fangwei
Department of Gynecologic Oncology, Women's Hospital, School of Medicine and MOE Laboratory of Biosystems Homeostasis & Protection, Life Sciences Institute, Zhejiang University, Hangzhou, China.
Zhejiang Key Laboratory of Molecular Cancer Biology, Life Sciences Institute, Zhejiang University, Hangzhou, China.
EMBO J. 2025 May 28. doi: 10.1038/s44318-025-00465-6.
Sister-chromatid cohesion mediated by the cohesin complex is critical for accurate chromosome segregation during mitosis. A key aspect of this process is the protection of cohesin at mitotic centromeres to resist spindle pulling-forces until anaphase onset. However, the mechanisms that prevent cohesin removal by its release-factor Wapl at centromeres remain incompletely understood. In this study, we identify ATRX, a chromatin remodeler of the SWI/SNF family, as a new binding protein of the cohesin complex. ATRX directly interacts with the cohesin accessory subunit Pds5B, antagonizing Wapl binding and thereby preventing premature release of centromeric cohesin. A mutation in ATRX that disrupts its interaction with Pds5B weakens centromeric cohesion and increases chromosome missegregation. Notably, centromere tethering of a Pds5B-binding fragment of ATRX, which lacks the ATPase domain, rescues cohesion defects in ATRX-depleted cells. Furthermore, Wapl depletion bypasses the requirement for ATRX, underscoring their antagonistic relationship. Together, these findings reveal a chromatin-remodeling-independent role for ATRX in maintaining centromeric cohesion by competitively inhibiting Wapl, providing new insights into the mechanisms that safeguard genomic stability.
由黏连蛋白复合体介导的姐妹染色单体黏连对于有丝分裂期间染色体的准确分离至关重要。这一过程的一个关键方面是在有丝分裂着丝粒处保护黏连蛋白，以抵抗纺锤体拉力，直到后期开始。然而，阻止黏连蛋白在着丝粒处被其释放因子Wapl去除的机制仍未完全了解。在本研究中，我们鉴定出SWI/SNF家族的染色质重塑因子ATRX是黏连蛋白复合体的一种新结合蛋白。ATRX直接与黏连蛋白辅助亚基Pds5B相互作用，拮抗Wapl的结合，从而防止着丝粒黏连蛋白过早释放。破坏ATRX与Pds5B相互作用的突变会削弱着丝粒黏连并增加染色体错分离。值得注意的是，缺乏ATP酶结构域的ATRX的Pds5B结合片段在着丝粒处的锚定挽救了ATRX缺失细胞中的黏连缺陷。此外，Wapl缺失绕过了对ATRX的需求，突出了它们的拮抗关系。总之，这些发现揭示了ATRX在通过竞争性抑制Wapl维持着丝粒黏连方面的非染色质重塑作用，为保障基因组稳定性的机制提供了新见解。
