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

ADRIAN CAMBINDO BOTTO; LUCIANA GIONO; MANUEL J MUÑOZ; NICOLÁS NIETO MORENO; ALBERTO R KORNBLIHTT

Montevideo

Congreso; X ALAMCTA congress: Congreso Internacional Asociación Latinoamericana Mutagénesis, Carcinogénesis y Teratogénesis Ambiental; 2016

We have previously found that UV irradiation promotes RNA polymerase II (RNAPII) hyperphosphorylation and subsequent changes in alternative splicing (AS). We show now that the UV effect is caused by damage to DNA only and that photolyase-mediated removal of cyclobutane pyrimidine dimers (CPDs) is sufficient to abrogate the global response to UV. We demonstrate that in skin cells RNAPII is the target, but not a sensor, of the signaling cascade initiated by CPDs. Evaluation of the roles of the xeroderma pigmentosum factors XPE, XPC, XPA, XPB, XPD, XPF and XPG, as well as of gap-filling DNA synthesis indicate that, after lesion recognition, the mechanism involves activation of the protein kinase ATR by repair intermediates known to contain ssDNA. Our results define the sequence UV-CPD-XP-ssDNA-ATR-RNAPII-AS as a new pathway linking global genome nucleotide excision repair (GG-NER) to the control of gene expression both at the transcription and RNA splicing levels.