染色体破碎大灾变是染色体不稳定性的一种灾难性事件，涉及局部染色体区域的严重裂解和重组。然而，其原因仍不清楚。在这里，我们展示了Ran GTP酶激活蛋白1(RanGAP1)的减少和失活普遍发生于人类骨肉瘤中，这与染色体破碎大灾变高发率有关。在快速扩张的小鼠骨前体细胞中，RanGAP1缺乏会引起chr1q的染色体破碎大灾变，Rb1的瞬时失活和p53的降解，进而导致DNA损伤修复的失败和超快速骨肉瘤形成。在有丝分裂中，RanGAP1锚定在着丝粒上，招募PP1-γ来对抗纺锤体装配检查点(SAC)的活性，并防止TOP2A的降解，从而维护染色单体解开状态。失去了RanGAP1会引起SAC的超活化和染色单体解开失败。这些发现表明RanGAP1维护有丝分裂染色体完整性，RanGAP1的丢失通过其对SAC和染色单体解开的直接影响以及对DNA损伤监测的次要影响推动肿瘤形成。版权所有©2022 Elsevier Inc.。保留所有权利。

Chromothripsis 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.