Translational reprogramming following UVB irradiation is mediated by DNA-PKcs and allows selective recruitment to the polysomes of mRNAs encoding DNA repair enzymes

Abstract

UVB-induced lesions in mammalian cellular DNA can, through the process of mutagenesis, lead to carcinogenesis. However, eukaryotic cells have evolved complex mechanisms of genomic surveillance and DNA damage repair to counteract the effects of UVB radiation. We show that following UVB DNA damage, there is an overall inhibition of protein synthesis and translational reprogramming. This reprogramming allows selective synthesis of DDR proteins, such as ERCC1, ERCC5, DDB1, XPA, XPD, and OGG1 and relies on upstream ORFs in the 59 untranslated region of these mRNAs. Experiments with DNA-PKcs-deficient cell lines and a specific DNA-PKcs inhibitor demonstrate that both the general repression of mRNA translation and the preferential translation of specific mRNAs depend on DNA-PKcs activity, and therefore our data establish a link between a key DNA damage signaling component and protein synthesis.[Keywords: DNA damage; translation; upstream ORF] Supplemental material is available at http://www.genesdev.org.

Heat Shock Protein 90α (Hsp90α) Is Phosphorylated in Response to DNA Damage and Accumulates in Repair Foci

“…It recognizes and binds to DSBs, regulates the correct alignment of the DNA ends, and controls the access of other DNA repair factors to the damaged DNA (8). Recent findings suggest that, in addition to its well established role in DNA repair in the nucleus, DNA-PK may be involved in the phosphorylation of cytoplasmic targets involved in cellular signaling pathways, such as UV-induced translational reprogramming (9), NFB activation (10,11), or the regulation of Akt/PKB (12). The implications of these functions are not yet well understood.…”

Transcriptional Repression of ATF4 Gene by CCAAT/Enhancer-binding Protein β (C/EBPβ) Differentially Regulates Integrated Stress Response

“…Activation of ATF4 transcription leads to more mRNA available for preferential translation during eIF2␣ϳP In response to UV irradiation, GCN2 phosphorylation of eIF2␣ lowers the levels of eIF2-GTP, resulting in reduced global translation. Additionally, eIF2␣ϳP leads to preferential translation of genes involved in repair of damaged DNA and those that thwart apoptosis, although the underlying mechanisms have not yet been determined (61). UV irradiation triggers repressed transcription of the ATF4 gene by increased C/EBP␤ association at the ATF4 promoter sequences between Ϫ1000 and Ϫ879 bp.…”

“…In the case of UV stress, there is repressed ATF4 expression, and induced eIF2␣ϳP can instead trigger preferential translation of alternative target mRNAs that facilitate DNA repair and enhance survival (Fig. 10A) (61). Selection of the precise target genes that are subject to preferential translation can be tailored to the individual stress condition, eliciting gene expression that is optimal for remedying the underlying cell damage.…”

In vivo radiation response of proneural glioma characterized by protective p53 transcriptional program and proneural-mesenchymal shift

“…Radiation-induced DNA damage has been reported to regulate translational efficiency both globally and in a transcript-specific manner (14,15). In glioma cell lines cultured in vitro, irradiation was reported to cause a much larger change in the translating pool of RNA than in total cellular RNA, suggesting a more important role for translational regulation than transcriptional regulation in the GBM radiation response (16).…”