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p21 is Responsible for Ionizing Radiation-induced Bypass of Mitosis

Xu Rui Zhang1, Yong Ai Liu1, Fang Sun1

  • 1Gansu Key Laboratory of Space Radiobiology, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730000, Gansu, China; University of Chinese Academy of Sciences, Beijing 100049, China.

Biomedical and Environmental Sciences : BES
|August 25, 2016
PubMed
Abstract

Insights

The protein p21 causes G2 arrest and prevents mitosis after radiation exposure in uveal melanoma cells. Depleting p21 allows damaged cells to enter mitosis, but they cannot divide properly.

Area of Science:

  • Cell Biology
  • Cancer Research
  • Radiation Oncology

Background:

  • Ionizing radiation (IR) induces cell cycle arrest to allow DNA repair.
  • The G2/M checkpoint is crucial for preventing the propagation of damaged DNA.
  • p21 is a key regulator of cell cycle progression.

Purpose of the Study:

  • To investigate the role of p21 in IR-induced G2/M transition and long-term G2 arrest.
  • To understand how p21 influences protein levels during cell cycle progression after irradiation.

Main Methods:

  • Western blot analysis of protein expression in 92-1 uveal melanoma cells.
  • siRNA-mediated depletion of p21.
  • Flow cytometry for cell cycle distribution analysis.
  • Histone H3 phosphorylation (Ser28) as an M-phase marker.
  • Senescence-associated-β-galactosidase (SA-β-gal) and Ki67 staining for senescence and proliferation assessment.

Main Results:

  • IR (5 Gy X-rays) increased p21 levels, decreased G2/M transition gene expression, and induced G2 arrest and senescence.
  • p21 depletion via siRNA rescued radiation-induced G2 arrest, promoting entry into mitosis.
  • Histone H3 phosphorylation at Ser28 was upregulated upon p21 knockdown.
  • Mitotic entry in p21-depleted cells with severe DNA damage led to failed cytokinesis and multinucleation.

Conclusions:

  • p21 mediates the downregulation of G2/M transition proteins and bypasses mitosis following irradiation.
  • siRNA-mediated p21 downregulation enables G2-arrested cells with significant DNA damage to enter mitosis.
  • This study provides the first evidence for p21's role in the bypass of mitosis.
Keywords:
DNA damageG2 arrestG2/M transitionIonizing radiation

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