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Pulsatile MAPK Signaling Modulates p53 Activity to Control Cell Fate Decisions at the G2 Checkpoint for DNA Damage

Siddharth De1, Callum Campbell1, Ashok R Venkitaraman1

  • 1Medical Research Council Cancer Unit, University of Cambridge, Hills Road, Cambridge CB2 0XZ, UK.

Cell Reports
|February 21, 2020
PubMed

Insights

Mitogen-activated protein kinase (MAPK) signaling controls cell fate at the G2 DNA damage checkpoint. MAPK activity influences p53 dynamics, determining whether cells arrest or evade senescence, impacting genomic integrity.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • Cell-autonomous p53 dynamics regulate G2 checkpoint arrest duration and outcome following DNA damage.
  • The G2 checkpoint is crucial for maintaining genomic integrity during cell proliferation.

Purpose of the Study:

  • To investigate the role of mitogen-activated protein kinase (MAPK) signaling in integrating extracellular cues with p53 dynamics at the G2 checkpoint.
  • To elucidate the mechanism by which MAPK signaling influences cell fate decisions at the G2 checkpoint.

Main Methods:

  • Utilized optogenetic tools and quantitative cell biochemistry.
  • Investigated MAPK activity oscillations dependent on ataxia-telangiectasia-mutated (ATM) kinase.
  • Analyzed the effects of MAPK inhibition and sustained signaling on p53 dynamics and G2 arrest.

Main Results:

  • Discovered transient oscillations in MAPK activity post-DNA damage, regulated by ATM kinase.
  • MAPK inhibition prolonged G2 arrest by altering p53 dynamics and gene expression.
  • Sustained MAPK signaling promoted CDC25C phosphorylation, leading to pro-mitotic kinase accumulation and evasion of prolonged G2 arrest and senescence.

Conclusions:

  • Proposed a model where MAPK signaling integrates extracellular cues with p53-mediated signals to safeguard genomic integrity.
  • Imbalance in this MAPK-mediated tumor-suppressive mechanism during oncogene-driven carcinogenesis may lead to genome instability.
Keywords:
DNA damage responseMAPK/ERK pathwaycellular decisionscheckpoint fidelitycheckpoint signallingp53signalling dynamics

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