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

Ian R. Powley, Alexander Kondrashov, Lucy A. Young, Helen C. Dobbyn, Kirsti Hill, Ian G. Cannell, Mark Stoneley, Yi Wen Kong, Julia A. Cotes, Graeme C M Smith, Ronald Wek, Christopher Hayes, Timothy W. Gant, Keith A. Spriggs, Martin Bushell, Anne E. Willis

Research output: Contribution to journalArticle

103 Citations (Scopus)

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 5′ 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.

Original languageEnglish
Pages (from-to)1207-1220
Number of pages14
JournalGenes and Development
Volume23
Issue number10
DOIs
StatePublished - May 15 2009

Fingerprint

DNA Repair Enzymes
Polyribosomes
DNA Damage
Messenger RNA
DNA
Protein Biosynthesis
5' Untranslated Regions
Radiation Effects
Eukaryotic Cells
Mutagenesis
DNA Repair
Open Reading Frames
Carcinogenesis
Proteins
Cell Line

Keywords

  • DNA damage
  • Translation
  • Upstream ORF

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology
  • Medicine(all)

Cite this

Translational reprogramming following UVB irradiation is mediated by DNA-PKcs and allows selective recruitment to the polysomes of mRNAs encoding DNA repair enzymes. / Powley, Ian R.; Kondrashov, Alexander; Young, Lucy A.; Dobbyn, Helen C.; Hill, Kirsti; Cannell, Ian G.; Stoneley, Mark; Kong, Yi Wen; Cotes, Julia A.; Smith, Graeme C M; Wek, Ronald; Hayes, Christopher; Gant, Timothy W.; Spriggs, Keith A.; Bushell, Martin; Willis, Anne E.

In: Genes and Development, Vol. 23, No. 10, 15.05.2009, p. 1207-1220.

Research output: Contribution to journalArticle

Powley, IR, Kondrashov, A, Young, LA, Dobbyn, HC, Hill, K, Cannell, IG, Stoneley, M, Kong, YW, Cotes, JA, Smith, GCM, Wek, R, Hayes, C, Gant, TW, Spriggs, KA, Bushell, M & Willis, AE 2009, 'Translational reprogramming following UVB irradiation is mediated by DNA-PKcs and allows selective recruitment to the polysomes of mRNAs encoding DNA repair enzymes', Genes and Development, vol. 23, no. 10, pp. 1207-1220. https://doi.org/10.1101/gad.516509
Powley, Ian R. ; Kondrashov, Alexander ; Young, Lucy A. ; Dobbyn, Helen C. ; Hill, Kirsti ; Cannell, Ian G. ; Stoneley, Mark ; Kong, Yi Wen ; Cotes, Julia A. ; Smith, Graeme C M ; Wek, Ronald ; Hayes, Christopher ; Gant, Timothy W. ; Spriggs, Keith A. ; Bushell, Martin ; Willis, Anne E. / Translational reprogramming following UVB irradiation is mediated by DNA-PKcs and allows selective recruitment to the polysomes of mRNAs encoding DNA repair enzymes. In: Genes and Development. 2009 ; Vol. 23, No. 10. pp. 1207-1220.
@article{62e804fdf3a745e4b06f2cb5bf146d4a,
title = "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 5′ 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",
author = "Powley, {Ian R.} and Alexander Kondrashov and Young, {Lucy A.} and Dobbyn, {Helen C.} and Kirsti Hill and Cannell, {Ian G.} and Mark Stoneley and Kong, {Yi Wen} and Cotes, {Julia A.} and Smith, {Graeme C M} and Ronald Wek and Christopher Hayes and Gant, {Timothy W.} and Spriggs, {Keith A.} and Martin Bushell and Willis, {Anne E.}",
year = "2009",
month = "5",
day = "15",
doi = "10.1101/gad.516509",
language = "English",
volume = "23",
pages = "1207--1220",
journal = "Genes and Development",
issn = "0890-9369",
publisher = "Cold Spring Harbor Laboratory Press",
number = "10",

}

TY - JOUR

T1 - Translational reprogramming following UVB irradiation is mediated by DNA-PKcs and allows selective recruitment to the polysomes of mRNAs encoding DNA repair enzymes

AU - Powley, Ian R.

AU - Kondrashov, Alexander

AU - Young, Lucy A.

AU - Dobbyn, Helen C.

AU - Hill, Kirsti

AU - Cannell, Ian G.

AU - Stoneley, Mark

AU - Kong, Yi Wen

AU - Cotes, Julia A.

AU - Smith, Graeme C M

AU - Wek, Ronald

AU - Hayes, Christopher

AU - Gant, Timothy W.

AU - Spriggs, Keith A.

AU - Bushell, Martin

AU - Willis, Anne E.

PY - 2009/5/15

Y1 - 2009/5/15

N2 - 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 5′ 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.

AB - 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 5′ 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.

KW - DNA damage

KW - Translation

KW - Upstream ORF

UR - http://www.scopus.com/inward/record.url?scp=66149137639&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=66149137639&partnerID=8YFLogxK

U2 - 10.1101/gad.516509

DO - 10.1101/gad.516509

M3 - Article

C2 - 19451221

AN - SCOPUS:66149137639

VL - 23

SP - 1207

EP - 1220

JO - Genes and Development

JF - Genes and Development

SN - 0890-9369

IS - 10

ER -