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.
Highlights
Persistent DNA damage induces profound alterations in gene expression that, in turn, influence tissue homeostasis, tumorigenesis, and cancer treatment outcome
To determine whether persistent DNA damage modulates nonsense-mediated RNA decay (NMD) activity, we treated confluent nontransformed human RPE1 cells with the DNA-damaging agent bleomycin (63 g/ml) for 24 h and allowed the cells to recover in the absence of bleomycin for 4 days
We found that persistent DNA damage, but not transient DNA damage, induces NMD repression and that this repression contributes to the stabilization of the mRNA of the transcription factor Activating transcription factor 3 (ATF3)
Summary
Persistent DNA damage induces profound alterations in gene expression that, in turn, influence tissue homeostasis, tumorigenesis, and cancer treatment outcome. Cence-associated secretory phenotype (SASP), a collection of secreted factors such as cytokines, chemokines, growth factors, and proteases [1, 3, 15] Both senescence and SASP directly impact the tumorigenesis process and cancer treatment outcome by influencing tumor cell growth and modifying the tumor microenvironment [2, 15,16,17,18,19,20,21,22]. These phenotypes and other responses to persistent DNA damage are a result of gene expression reprogramming brought about by signaling molecules such as p38, which regulate transcription, RNA stability, and translation [17, 23]. NMD helps coordinate the cellular response to several forms of stress, including amino acid deprivation, hypoxia, and endoplasmic reticulum stress, by governing the expression levels of many stress response genes
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