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MASTL(Greatwall) regulates DNA damage responses by coordinating mitotic entry after checkpoint recovery and APC/C

Po Yee Wong1, Hoi Tang Ma1, Hyun-jung Lee1

  • 1Division of Life Science, Center for Cancer Research, and State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong.

Scientific Reports
|March 1, 2016
PubMed

Insights

The Greatwall kinase (MASTL) controls cell cycle progression after DNA damage. Precise MASTL regulation ensures proper timing of mitosis entry, preventing genomic instability.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Genetics

Background:

  • The G2 DNA damage checkpoint is crucial for controlling the transition from G2 phase to mitosis.
  • The Greatwall kinase (MASTL) regulates G2-mitosis transition by inhibiting PP2A phosphatase activity through ARPP19 and ENSA.
  • Maintaining genome integrity after DNA damage is essential for preventing uncontrolled cell proliferation.

Purpose of the Study:

  • To investigate the role of MASTL in maintaining genome integrity following DNA damage.
  • To determine how MASTL influences the timing of mitotic entry and cell fate after DNA damage.
  • To elucidate the mechanism by which MASTL couples DNA damage responses to cell cycle progression.

Main Methods:

  • Investigated MASTL's role in DNA damage response and repair.
  • Assessed the impact of MASTL activity on mitotic entry timing using cell cycle analysis.
  • Examined the effect of MASTL, ARPP19, and ENSA modulation on CDK1 phosphorylation and APC/C activation.
  • Monitored cell fate following DNA damage under varying MASTL expression levels.

Main Results:

  • MASTL is critical for maintaining genome integrity after DNA damage, independent of DNA damage response and repair activation.
  • MASTL activity dictates the timing of mitotic entry; constitutive MASTL accelerates it, while MASTL or ARPP19/ENSA downregulation delays it.
  • Premature APC/C activation was observed, leading to cells bypassing mitosis and entering G1 directly from G2.
  • CDK1(Tyr15) dephosphorylation was promoted by constitutively active MASTL, accelerating mitotic entry.

Conclusions:

  • Precise control of MASTL activity is essential for coupling DNA damage checkpoints to mitosis.
  • MASTL regulates the rate of mitotic entry and APC/C activation, thereby influencing cell fate after DNA damage.
  • Dysregulation of MASTL can lead to genomic instability by disrupting the normal G2-mitosis transition and cell cycle progression.

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