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p38 MAPK inhibits nonsense-mediated RNA decay in response to persistent DNA damage in noncycling cells

Andrew Nickless1, Abigael Cheruiyot1, Kevin C Flanagan1

  • 1From the Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri 63110 and.

The Journal of Biological Chemistry
|August 3, 2017
PubMed

Insights

Persistent DNA damage halts nonsense-mediated RNA decay (NMD) in noncycling cells. This process, regulated by p38α MAPK, impacts gene expression and stabilizing ATF3, crucial for cellular stress response.

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Genetics

Background:

  • Persistent DNA damage significantly alters gene expression, affecting tissue homeostasis, tumorigenesis, and cancer treatment.
  • The precise mechanisms driving gene expression reprogramming due to persistent DNA damage are not fully understood.

Purpose of the Study:

  • To elucidate the molecular mechanisms underlying gene expression changes induced by persistent DNA damage.
  • To investigate the role of nonsense-mediated RNA decay (NMD) in response to DNA damage.

Main Methods:

  • Utilized a bioluminescence-based reporter system to monitor RNA decay.
  • Employed molecular biology techniques to study protein activity and gene regulation.
  • Investigated the involvement of p38α MAPK and ATF3 in the DNA damage response.

Main Results:

  • Persistent DNA damage was found to inhibit nonsense-mediated RNA decay (NMD) in noncycling cells.
  • NMD suppression was dependent on the activity of p38α MAPK.
  • Activating transcription factor 3 (ATF3) stabilization occurred in a manner dependent on both p38α and NMD.

Conclusions:

  • A novel p38α-dependent pathway regulates NMD activity in response to persistent DNA damage.
  • This pathway controls the expression of ATF3, a key stress-inducible transcription factor, in damaged cells.
Keywords:
ATF3DNA damage responsegene expressionmRNA decaynonsense-mediated RNA decayp38persistent DNA damagesenescence

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