UV-induced DNA damage affects alternative splicing patterns: a new role for repair factors

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

BsAs

Congreso; XIX Congreso Argentino de Toxicología; 2015

The most common UV-induced DNA lesions in living cells are cyclobutane pyrimidine dimers (CPDs) and 6-4 pyrimidine-pyrimidone photoproducts [(6-4)PPs], both of which are repaired by the Nucleotide Excision Repair (NER) system, which consists of two distinct sub pathways: Global Genome Repair (GGR) and Transcription Coupled-Repair (TCR). Here we show that these DNA lesions are sufficient to initiate the global regulation of alternative splicing (AS) in skin cells through the phosphorylation of the carboxy terminal domain of RNA polymerase II, without the involvement of any other damaged biomolecule. We ruled out the involvement of TCR in the alternative splicing response but, in contrast, we found that the lesion recognition factor XPE, involved in GGR and mutated in xeroderma pigmentosum, also participates in the modulation of AS. Furthermore, we demonstrate that CPDs and (6-4)PPs affect different AS events (ASEs) and therefore are not only structurally but also functionally different DNA lesions.