| First Author | Gong Y | Year | 2023 |
| Journal | Dev Cell | Volume | 58 |
| Issue | 3 | Pages | 192-210.e11 |
| PubMed ID | 36696903 | Mgi Jnum | J:333345 |
| Mgi Id | MGI:7437260 | Doi | 10.1016/j.devcel.2022.12.012 |
| Citation | Gong Y, et al. (2023) Loss of RanGAP1 drives chromosome instability and rapid tumorigenesis of osteosarcoma. Dev Cell 58(3):192-210.e11 |
| abstractText | 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-gamma 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. |
