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. [Display omitted] • Loss of RanGAP1 in osteoprogenitors drives spontaneous osteosarcoma • Loss of RanGAP1 causes CIN and chromothripsis by overactivating the mitotic checkpoint • Loss of RanGAP1 rapidly inactivates p53 and Rb1, impairing DNA damage surveillance • Expression of RanGAP1 correlates with that of Rb1 in pan-cancer samples Gong et al. show here that loss of RanGAP1 overactivates the mitotic checkpoint, resulting in chromosome crisis and failure in DNA damage repair. These defects ultimately lead to ultrafast tumorigenesis of osteosarcoma, which resembles the onset age and sites of pediatric osteosarcoma. [ABSTRACT FROM AUTHOR]