Major roles of 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 th...

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Detalles Bibliográficos
Autores: Muñoz, Manuel Javier, Nieto Moreno, Nicolás, Giono, Luciana Eugenia, Cambindo Botto, Adrian Edgardo, Dujardin, Gwendal, Bastianello, Giulia, Lavore, Stefania, Torres-Méndez, Antonio, Menck, Carlos FM, Blencowe, Benjamin, Irimia, Manuel, Foiani, Marco, Kornblihtt, Alberto Rodolfo
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2017
País:Argentina
Institución:Consejo Nacional de Investigaciones Científicas y Técnicas
Repositorio:CONICET Digital (CONICET)
Idioma:inglés
OAI Identifier:oai:ri.conicet.gov.ar:11336/67718
Acceso en línea:http://hdl.handle.net/11336/67718
Access Level:acceso abierto
Palabra clave:ALTERNATIVE SPLICING
ATR
CYCLOBUTANE PYRIMIDINE DIMERS
DNA DAMAGE
GLOBAL GENOME REPAIR
NUCLEOTIDE EXCISION REPAIR
POTOROUS PHOTOLYASE
UV IRRADIATION
https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
Descripción
Sumario: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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