Guangdong Provincial Key Laboratory of Bone and Joint Degeneration Diseases, Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China; Affiliated Dongguan Hospital, Southern Medical University, Dongguan 523058, China.
Guangdong Provincial Key Laboratory of Bone and Joint Degeneration Diseases, Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China.
Dev Cell. 2023 Feb 6;58(3):192-210.e11. doi: 10.1016/j.devcel.2022.12.012. Epub 2023 Jan 24.
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.
染色体重排是一种涉及局部染色体区域剧烈碎裂和重排的灾难性染色体不稳定性事件。然而，其原因仍不清楚。在这里，我们表明，Ran GTPase 激活蛋白 1（RanGAP1）的减少和失活在人类骨肉瘤中普遍存在，这与染色体重排的高发生率有关。在快速扩增的小鼠成骨前体细胞中，RanGAP1 缺失导致 chr1q 发生染色体重排，Rb1 立即失活和 p53 降解，随后导致 DNA 损伤修复失败，并迅速引发骨肉瘤肿瘤发生。在有丝分裂过程中，RanGAP1 锚定在动粒上，在那里它招募 PP1-γ 来抵消纺锤体组装检查点（SAC）的活性并防止 TOP2A 降解，从而保护染色单体的解旋。RanGAP1 的丢失会导致 SAC 过度激活和染色单体解旋失败。这些发现表明，RanGAP1 维持有丝分裂染色体的完整性，RanGAP1 的缺失通过其对 SAC 和解旋的直接作用以及对 DNA 损伤监测的次级作用驱动肿瘤发生。
