Yan Gong, Shitian Zou, Daizhao Deng, Liang Wang, Hongling Hu, Zeyou Qiu, Tiantian Wei, Panpan Yang, Jielong Zhou, Yu Zhang, Weiliang Zhu, Xiaoling Xie, Zhengquan Liao, Jun Yang, Sheng Zhang, Anling Liu, Yu Jiang, Zhipeng Zou, Xiaochun Bai
Developmental cell 2023 Feb 06Chromothripsis is a catastrophic event of chromosomal instability that involves intensive fragmentation and rearrangements within localized chromosomal regions. However, its cause remains unclear. Here, we show that reduction and inactivation of Ran GTPase-activating protein 1 (RanGAP1) commonly occur in human osteosarcoma, which is associated with a high rate of chromothripsis. In rapidly expanding mouse osteoprogenitors, RanGAP1 deficiency causes chromothripsis in chr1q, instant inactivation of Rb1 and degradation of p53, consequent failure in DNA damage repair, and ultrafast osteosarcoma tumorigenesis. During mitosis, RanGAP1 anchors to the kinetochore, where it recruits PP1-γ to counteract the activity of the spindle-assembly checkpoint (SAC) and prevents TOP2A degradation, thus safeguarding chromatid decatenation. Loss of RanGAP1 causes SAC hyperactivation and chromatid decatenation failure. These findings demonstrate that RanGAP1 maintains mitotic chromosome integrity and that RanGAP1 loss drives tumorigenesis through its direct effects on SAC and decatenation and secondary effects on DNA damage surveillance. Copyright © 2022 Elsevier Inc. All rights reserved.
Yan Gong, Shitian Zou, Daizhao Deng, Liang Wang, Hongling Hu, Zeyou Qiu, Tiantian Wei, Panpan Yang, Jielong Zhou, Yu Zhang, Weiliang Zhu, Xiaoling Xie, Zhengquan Liao, Jun Yang, Sheng Zhang, Anling Liu, Yu Jiang, Zhipeng Zou, Xiaochun Bai. Loss of RanGAP1 drives chromosome instability and rapid tumorigenesis of osteosarcoma. Developmental cell. 2023 Feb 06;58(3):192-210.e11
PMID: 36696903
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