“UV irradiation, DNA damage and alternative splicing”

MUÑOZ M.J.

Edinburgh

Seminario; MRC Human Genetics Unit, University of Edinburgh, Western General Hospital. International seminar.; 2012

UV irradiation, DNA damage and alternative splicing Manuel J. Muñoz Laboratorio de Fisiología y Biología Molecular, FCEN and IFIBYNE, UBA-CONICET, Buenos Aires, Argentina. mmunoz@fbmc.fcen.uba.ar DNA is the only biopolymer that is neither disposable nor recyclable, and therefore must be repaired when damaged. DNA damage triggers specific intracellular signal cascades, lesion repair mechanisms and gene regulatory events that may result in cell cycle arrest or apoptosis. Transcriptional regulation and alternative pre-mRNA splicing have been identified as crucial targets of signal cascades triggered by DNA damage. We have previously shown that UV irradiation (UVC, 254 nm) causes the hyperphosphorylation of the carboxy terminal domain (CTD) of RNA polymerase II (pol II) large subunit, which slows transcriptional elongation rate and affects alternative splicing of a subset of genes through the kinetic coupling of transcription and splicing. UV mutagenesis is a critical step in the generation of different forms of skin cancer, which develops almost exclusively in sun exposed areas. Since UVC radiation is fully filtered by the ozone layer, we are extending our studies to UVB light (305 nm), the most harmful solar radiation that reaches the Earth’s surface. Consistent with our model, we found that UVB irradiation of human keratinocytes in culture promotes CTD hyperphosphorylation being this modification necessary for the observed changes in AS. Finally, while both UVC and UVB lights cause similar types of mutagenic DNA lesions, i.e., cyclobutane pyrimidine dimers (CPD) and (6-4) photo-products (6-4 PP), the relative distribution of these lesions varies with the kind of UV light. Transcriptome analysis of UVC and UVB treated keratinocytes will shed light on specific CPD or 6-4 PP response pathways.