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Loss of RanGAP1 drives chromosome instability and rapid tumorigenesis of osteosarcoma

Yan Gong1, Shitian Zou2, Daizhao Deng2

  • 1Guangdong 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.

Developmental Cell
|January 25, 2023
PubMed

Insights

Loss of Ran GTPase-activating protein 1 (RanGAP1) causes chromothripsis and ultrafast osteosarcoma development by disrupting mitotic chromosome integrity and DNA damage repair. This highlights RanGAP1

Area of Science:

  • Genetics
  • Cell Biology
  • Cancer Research

Background:

  • Chromothripsis, a complex chromosomal rearrangement, is a hallmark of genomic instability but its origins are poorly understood.
  • Osteosarcoma exhibits a high frequency of chromothripsis, suggesting a link between this cancer type and the underlying mechanisms of chromosomal instability.

Purpose of the Study:

  • To investigate the role of Ran GTPase-activating protein 1 (RanGAP1) in the pathogenesis of osteosarcoma.
  • To elucidate the molecular mechanisms by which RanGAP1 deficiency contributes to chromothripsis and tumorigenesis.

Main Methods:

  • Analysis of RanGAP1 expression in human osteosarcoma samples.
  • Generation of a mouse model with RanGAP1-deficient osteoprogenitors.
  • Mitotic analysis, including kinetochore-microtubule interactions and spindle-assembly checkpoint (SAC) activity.
  • Assessment of DNA damage repair pathways and tumor development.

Main Results:

  • Reduced and inactivated RanGAP1 is common in human osteosarcoma and associated with high chromothripsis rates.
  • RanGAP1 deficiency in mouse osteoprogenitors induced chromothripsis, Rb1 inactivation, p53 degradation, and rapid osteosarcoma formation.
  • Loss of RanGAP1 led to kinetochore dysfunction, SAC hyperactivation, and failed chromatid decatenation during mitosis.

Conclusions:

  • RanGAP1 is essential for maintaining mitotic chromosome integrity.
  • RanGAP1 loss drives osteosarcoma tumorigenesis via compromised SAC function, decatenation failure, and impaired DNA damage surveillance.
Keywords:
RanGAP1aneuploidchromatid decatenationchromosome instabilitymitotic checkpointosteosarcoma

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