Major Roles for Pyrimidine Dimers, Nucleotide Excision Repair, and ATR in the Alternative Splicing Response to UV Irradiation.

We have previously found that UV irradiation promotes RNA polymerase II (RNAPII) hyperphosphorylation and subsequent changes in alternative splicing (AS). We show now that UV-induced DNA damage is not only necessary but sufficient to trigger the AS response and that photolyase-mediated removal of the most abundant class of pyrimidine dimers (PDs) abrogates the global response to UV. We demonstrate that, in keratinocytes, RNAPII is the target, but not a sensor, of the signaling cascade initiated by PDs. The UV effect is enhanced by inhibition of gap-filling DNA synthesis, the last step in the nucleotide excision repair pathway (NER), and reduced by the absence of XPE, the main NER sensor of PDs. The mechanism involves activation of the protein kinase ATR that mediates the UV-induced RNAPII hyperphosphorylation. Our results define the sequence UV-PDs-NER-ATR-RNAPII-AS as a pathway linking DNA damage repair to the control of both RNAPII phosphorylation and AS regulation.

• Publication year

  2017

• Venue

  Cell Reports

• Publication date

  2017-03-21

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1016/j.celrep.2017.02.066PMID 28329680
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• ATR Kinase Inhibition Protects Non-cycling Cells from the Lethal Effects of DNA Damage and Transcription Stress*

  2016cited by this paper
• The core spliceosome as target and effector of non-canonical ATM signaling

  2015cited by this paper
• Identification of Cyclobutane Pyrimidine Dimer-Responsive Genes Using UVB-Irradiated Human Keratinocytes Transfected with In Vitro-Synthesized Photolyase mRNA

  2015cited by this paper
• Understanding nucleotide excision repair and its roles in cancer and ageing

  2014cited by this paper
• How slow RNA polymerase II elongation favors alternative exon skipping.

  2014cited by this paper
• Pre-mRNA splicing is facilitated by an optimal RNA polymerase II elongation rate

  2014cited by this paper
• Xeroderma pigmentosum complementation group C protein (XPC) serves as a general sensor of damaged DNA.

  2013cited by this paper
• Alternative splicing: a pivotal step between eukaryotic transcription and translation

  2013cited by this paper
• Tissue-specific alternative splicing remodels protein-protein interaction networks.

  2012cited by this paper
• Ultraviolet radiation damages self noncoding RNA and is detected by TLR3

  2012cited by this paper
• UV-induced photolesions elicit ATR-kinase-dependent signaling in non-cycling cells through nucleotide excision repair-dependent and -independent pathways

  2011cited by this paper
• Ganglion-specific splicing of TRPV1 underlies infrared sensation in vampire bats

  2011cited by this paper
• Wavelength dependence of ultraviolet radiation‐induced DNA damage as determined by laser irradiation suggests that cyclobutane pyrimidine dimers are the principal DNA lesions produced by terrestrial sunlight

  2011cited by this paper
• Peripheral SMN restoration is essential for long-term rescue of a severe SMA mouse model

  2011cited by this paper
• Global impact of RNA polymerase II elongation inhibition on alternative splicing regulation.

  2011cited by this paper
• Deciphering the splicing code

  2010cited by this paper
• The carboxy terminal domain of RNA polymerase II and alternative splicing.

  2010cited by this paper
• A Ubiquitin-Binding Domain in Cockayne Syndrome B Required for Transcription-Coupled Nucleotide Excision Repair

  2010cited by this paper
• CDK12 is a transcription elongation-associated CTD kinase, the metazoan ortholog of yeast Ctk1.

  2010cited by this paper
• Nucleotide excision repair–induced H2A ubiquitination is dependent on MDC1 and RNF8 and reveals a universal DNA damage response

  2009cited by this paper
• DNA damage regulates alternative splicing through inhibition of RNA polymerase II elongation.

  2009cited by this paper
• CPDs and 6-4PPs play different roles in UV-induced cell death in normal and NER-deficient human cells.

  2008cited by this paper
• Differential repair of UVB-induced cyclobutane pyrimidine dimers in cultured human skin cells and whole human skin.

  2008cited by this paper
• Replication independent ATR signalling leads to G2/M arrest requiring Nbs1, 53BP1 and MDC1.

  2008cited by this paper
• ATM and ATR Substrate Analysis Reveals Extensive Protein Networks Responsive to DNA Damage

  2007cited by this paper
• Cell surface expression of melanocortin-1 receptor on HaCaT keratinocytes and α-melanocortin stimulation do not affect the formation and repair of UVB-induced DNA photoproducts

  2007cited by this paper
• Perturbed gap-filling synthesis in nucleotide excision repair causes histone H2AX phosphorylation in human quiescent cells

  2007cited by this paper
• H2AX phosphorylation after UV irradiation is triggered by DNA repair intermediates and is mediated by the ATR kinase.

  2007cited by this paper
• Cell type and DNA damage specific response of human skin cells to environmental agents.

  2007cited by this paper
• ATR‐dependent phosphorylation and activation of ATM in response to UV treatment or replication fork stalling

  2006cited by this paper
• The connection between splicing and cancer

  2006cited by this paper
• RNA polymerase II C-terminal domain mediates regulation of alternative splicing by SRp20

  2006cited by this paper
• Cellular and molecular events leading to the development of skin cancer.

  2005cited by this paper
• Differential role of transcription-coupled repair in UVB-induced response of human fibroblasts and keratinocytes.

  2005cited by this paper
• Xeroderma Pigmentosum Complementation Group E Protein (XPE/DDB2): Purification of Various Complexes of XPE and Analyses of Their Damaged DNA Binding and Putative DNA Repair Properties

  2005cited by this paper
• Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints.

  2004cited by this paper
• A slow RNA polymerase II affects alternative splicing in vivo.

  2003cited by this paper
• Distribution and repair of bipyrimidine photoproducts in solar UV-irradiated mammalian cells. Possible role of Dewar photoproducts in solar mutagenesis.

  2000cited by this paper

• How Do ROS Induce NETosis? Oxidative DNA Damage, DNA Repair, and Chromatin Decondensation

  2024cites this paper
• RNA polymerase II degradation triggered by DNA repair occurs in trans and independently of how the lesion is recognized

  2024cites this paper
• Elongation roadblocks mediated by dCas9 across human genes modulate transcription and nascent RNA processing

  2023cites this paper
• Transcription-Coupled Nucleotide Excision Repair and the Transcriptional Response to UV-Induced DNA Damage.

  2023cites this paper
• Short-Term UVB Irradiation Leads to Persistent DNA Damage in Limbal Epithelial Stem Cells, Partially Reversed by DNA Repairing Enzymes

  2023cites this paper
• Nasal Ala Reconstruction with Mid-Forehead Flap in a Patient with Xeroderma Pigmentosum: a Case Report

  2022cites this paper
• UV Protection in the Cornea: Failure and Rescue

  2022cites this paper
• Cellular fractionation reveals transcriptome responses of human fibroblasts to UV-C irradiation

  2022cites this paper
• DNA Damage Regulates the Functions of the RNA Binding Protein Sam68 through ATM-Dependent Phosphorylation

  2022cites this paper
• Transcription and genome integrity.

  2022cites this paper
• DNA damage-induced transcription stress triggers the genome-wide degradation of promoter-bound Pol II

  2022cites this paper
• Counteracting chromatin effects of a splicing-correcting antisense oligonucleotide improves its therapeutic efficacy in spinal muscular atrophy.

  2022cites this paper
• Multi-omic analysis of altered transcriptome and epigenetic signatures in the UV-induced DNA damage response.

  2021cites this paper
• Coordination of RNA Processing Regulation by Signal Transduction Pathways

  2021cites this paper
• U5 snRNA Interactions With Exons Ensure Splicing Precision

  2021cites this paper
• Reciprocal regulation between alternative splicing and the DNA damage response

  2020influential citation
• Alternative Splicing and DNA Damage Response in Plants

  2020cites this paper
• GSK-3 is an RNA polymerase II phospho-CTD kinase

  2020cites this paper
• Intrinsic Regulatory Role of RNA Structural Arrangement in Alternative Splicing Control

  2020cites this paper
• Linking transcription, RNA polymerase II elongation and alternative splicing.

  2020cites this paper
• Transcription blockage by DNA damage in nucleotide excision repair-related neurological dysfunctions.

  2020cites this paper
• Damage removal and gap filling in nucleotide excision repair.

  2019cites this paper
• ATR Kinase Activity Limits Mutagenesis and Promotes the Clonogenic Survival of Quiescent Human Keratinocytes Exposed to UVB Radiation

  2019cites this paper
• The DNA damage response to transcription stress

  2019cites this paper
• Genome draft of the Arabidopsis relative Pachycladon cheesemanii reveals novel strategies to tolerate New Zealand’s high ultraviolet B radiation environment

  2019cites this paper
• Opsin 3 is a key regulator of ultraviolet A‐induced photoageing in human dermal fibroblast cells

  2019cites this paper
• Regulation of ATR activity via the RNA polymerase II associated factors CDC73 and PNUTS-PP1

  2018cites this paper
• Origin of exon skipping-rich transcriptomes in animals driven by evolution of gene architecture

  2018cites this paper
• What happens at the lesion does not stay at the lesion: Transcription-coupled nucleotide excision repair and the effects of DNA damage on transcription in cis and trans.

  2018cites this paper
• UV-driven hydroxyl radical oxidation of tris(2-chloroethyl) phosphate: Intermediate products and residual toxicity.

  2018cites this paper
• The Cellular Response to Transcription-Blocking DNA Damage

  2018cites this paper
• Coupling between nucleotide excision repair and gene expression

  2018influential citation
• Transcription elongation rate affects nascent histone pre-mRNA folding and 3′ end processing

  2018cites this paper
• The ATR kinase of Trypanosoma brucei links DNA damage signalling and monoallelic control of surface antigen gene expression during antigenic variation

  2018cites this paper
• Regulation of ATR activity by the RNA polymerase II phosphatase PNUTS-PP1

  2018cites this paper
• Roles of UVA radiation and DNA damage responses in melanoma pathogenesis

  2018cites this paper
• The melanocortin signaling cAMP axis accelerates repair and reduces mutagenesis of platinum-induced DNA damage

  2017cites this paper
• DNA damage-induced ATM- and Rad-3-related (ATR) kinase activation in non-replicating cells is regulated by the XPB subunit of transcription factor IIH (TFIIH)

  2017cites this paper
• The Role of DNA Repair in the Onset and Therapy of Ovarian Cancer

  2017cites this paper
• Transcriptome analysis of hypoxic cancer cells uncovers intron retention in EIF2B5 as a mechanism to inhibit translation

  2017cites this paper
• Signaling Pathways Driving Aberrant Splicing in Cancer Cells

  2017cites this paper
• DNA damage-induced ATR kinase activation in non-replicating cells is regulated by the XPB subunit of transcription factor II-H (TFIIH)

  2017cites this paper