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Mitosis-specific acetylation tunes Ran effector binding for chromosome segregation
Xiaoling Bao 1,† , Heng Liu 1,† , Xing Liu 2 , Ke Ruan 1 , Yonghui Zhang 1 , Zhiyong Zhang 1 , Qi Hu 1 , Ying Liu 1 , Saima Akram 2 , Jiahai Zhang 1 , Qingguo Gong 1 , Wenwen Wang 2 , Xiao Yuan 3 , Jian Li 4 ,Lingli Zhao 4 , Zhen Dou 2 , Ruijun Tian 3 , Xuebiao Yao 2, *, Jihui Wu 1, * , and Yunyu Shi 1, *
1 Hefei National Laboratory for Physical Sciences at Microscale, and School of Life Sciences, University of Science and Technology of China, Hefei 230027,China
2 Center of Excellence in Molecular Cell Sciences, Chinese Academy of Sciences & Anhui Key Laboratory for Cellular Dynamics and Chemical Biology, Hefei 230027, China
3 Southern University of Science & Technology, Shenzhen 518055, China
4 Keck Center for Molecular Imaging, Morehouse School of Medicine, Atlanta, GA 30310, USA
These authors contributed equally to this work. *Correspondence to:Xuebiao Yao, E-mail: yaoxb@ustc.edu.cn; Jihui Wu, E-mail: wujihui@ustc.edu.cn; Yunyu Shi, E-mail: yyshi@ustc.edu.cn
J Mol Cell Biol, Volume 10, Issue 1, February 2018, Pages 18-32  https://doi.org/10.1093/jmcb/mjx045
Keyword: Ran-GTP, Lys134 acetylation, TIP60, mitosis, chromosome segregation, NMR
Stable transmission of genetic information during cell division requires faithful mitotic spindle assembly and chromosome segregation. The Ran GTPase plays a key role in mitotic spindle assembly. However, how the generation of a chemical gradient of Ran-GTP at the spindle is coupled to mitotic post-translational modifications has never been characterized. Here, we solved the complex structure of Ran with the nucleotide release factor Mog1 and delineated a novel mitosis-specific acetylation-regulated Ran–Mog1 interaction during chromosome segregation. Our structure-guided functional analyses revealed that Mog1 competes with RCC1 for Ran binding in a GTP/GDP-dependent manner. Biochemical characterization demonstrated that Mog1-bound Ran prevents RCC1 binding and subsequent GTP loading. Surprisingly, Ran is a bona fide substrate of TIP60, and the acetylation of Lys134 by TIP60 liberates Mog1 from Ran binding during mitosis. Importantly, this acetylation-elicited switch of Ran binding to RCC1 promotes high level of Ran-GTP, which is essential for chromosome alignment. These results establish a previously uncharacterized regulatory mechanism in which TIP60 provides a homeostatic control of Ran-GTP level by tuning Ran effector binding for chromosome segregation in mitosis.