Journal
CELL REPORTS
Volume 18, Issue 12, Pages 2868-2879Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2017.02.066
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Funding
- Agencia Nacional de Promocion Cientifica y Tecnologica of Argentina [PICT-2011 1617, PICT-2014 2582]
- Universidad de Buenos Aires (UBACYT) [20020130100152BA]
- Marie Curie International Outgoing Fellowship within the EU Seventh Framework Programme for Research and Technological Development [275632]
- Canadian Institutes of Health Research [148434]
- European Research Council [ERC-StG-LS2-637591]
- Ministerio de Economia y Competitividad (MINECO) [BFU2014-55076-P]
- Spanish Ministry of Economy and Competitiveness
- Associazione Italiana per la Ricerca sul Cancro (AIRC)
- Telethon-Italy
- University of Milan
- Consejo Nacional de Investigaciones Cientificas y Tecnicas of Argentina (CONICET)
- Alberto J. Roemmers Foundation
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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.
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