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J Biol Chem. 2017 Sep 15;292(37):15266-15276. doi: 10.1074/jbc.M117.787846. Epub 2017 Aug 1.

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

Author information

1
From the Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri 63110 and.
2
the Department of Cancer Systems Imaging, University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030.
3
From the Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri 63110 and zyou@wustl.edu.

Abstract

Persistent DNA damage induces profound alterations in gene expression that, in turn, influence tissue homeostasis, tumorigenesis, and cancer treatment outcome. However, the underlying mechanism for gene expression reprogramming induced by persistent DNA damage remains poorly understood. Here, using a highly effective bioluminescence-based reporter system and other tools, we report that persistent DNA damage inhibits nonsense-mediated RNA decay (NMD), an RNA surveillance and gene-regulatory pathway, in noncycling cells. NMD suppression by persistent DNA damage required the activity of the p38α MAPK. Activating transcription factor 3 (ATF3), an NMD target and a key stress-inducible transcription factor, was stabilized in a p38α- and NMD-dependent manner following persistent DNA damage. Our results reveal a novel p38α-dependent pathway that regulates NMD activity in response to persistent DNA damage, which, in turn, controls ATF3 expression in affected cells.

KEYWORDS:

ATF3; DNA damage response; gene expression; mRNA decay; nonsense-mediated RNA decay; p38; persistent DNA damage; senescence

PMID:
28765281
PMCID:
PMC5602387
DOI:
10.1074/jbc.M117.787846
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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