1. Academic Validation
  2. Mitosis-specific acetylation tunes Ran effector binding for chromosome segregation

Mitosis-specific acetylation tunes Ran effector binding for chromosome segregation

  • J Mol Cell Biol. 2018 Feb 1;10(1):18-32. doi: 10.1093/jmcb/mjx045.
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 Yunyu Shi 1
Affiliations

Affiliations

  • 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.
Abstract

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.

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