Major roles of for pyrimidine dimers, nucleotide excision repair and ATR in the alternative splicing response to UV irradiation

LUCIANA E. GIONO; GIULIA BASTIANELLO; CARLOS F. M. MENCH; NICOLÁS NIETO MORENO; MANUEL J. MUÑOZ; MARCO FOIANI; GWENDAL DUJARDIN; ADRIÁN E. CAMBINDO BOTTO; STEFANIA LAVORE; ANTONIO TORRES-MÉNDEZ; MANUEL IRIMIA; BENJAMIN J. BLENCOWE; ALBERTO R. KORNBLIHTT

Cell Reports

Cell Press

Año: 2017 vol. 18 p. 2868 - 2879

2211-1247

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 new pathway linking DNA damage repair to the control of both RNAPII phosphorylation and AS regulation.