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ATR/Chk1/Smurf1 pathway determines cell fate after DNA damage by controlling RhoB abundance

Meilin Wang1, Lei Guo1, Qingang Wu1

  • 1State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China.

Nature Communications
|September 25, 2014
PubMed

Insights

The DNA damage response involves ATR/Chk1 signaling. This study reveals that Smurf1 degrades the tumor suppressor RhoB, controlling apoptosis after DNA damage and potentially impacting cancer development.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Cancer Research

Background:

  • The DNA damage response is crucial for maintaining genomic stability.
  • Signaling pathways like ATR/Chk1 and ATM/Chk2 are key regulators of this response.
  • RhoB, a small GTPase, acts as a tumor suppressor by promoting apoptosis in transformed cells.

Purpose of the Study:

  • To elucidate the role of the E3 ubiquitin ligase Smurf1 in the DNA damage response.
  • To investigate the mechanism by which Smurf1 influences cell apoptosis downstream of ATR/Chk1 signaling.
  • To identify novel pathways regulating cell fate following DNA damage.

Main Methods:

  • Investigated Smurf1's role in RhoB degradation.
  • Utilized DNA damaging agents (UV light, methyl methanesulfonate).
  • Analyzed Chk1 activation, Smurf1 phosphorylation, and RhoB accumulation.
  • Assessed apoptosis rates under conditions of altered Smurf1 or Chk1 activity.

Main Results:

  • Smurf1 targets RhoB for degradation, regulating its basal levels.
  • DNA damage activates Chk1, leading to Smurf1 phosphorylation and self-degradation.
  • This Smurf1 degradation results in RhoB accumulation and promotes apoptosis.
  • Inhibition of RhoB or Smurf1 self-degradation significantly reduces apoptosis.

Conclusions:

  • A novel ATR/Chk1/Smurf1/RhoB pathway dictates cell fate after DNA damage.
  • Smurf1-mediated RhoB degradation is a critical step in DNA damage-induced apoptosis.
  • Aberrant Smurf1 upregulation may promote tumorigenesis by excessive RhoB degradation.

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