CONICET | Buscador de Institutos y Recursos Humanos

Ultraviolet B (UVB) Induced DNA Damage Affects Alternative Splicing in Skin Cells Nicolás Nieto Moreno, Gwendal Dujardin, Alberto R. Kornblihtt and Manuel J. Muñoz Laboratorio de Fisiología y Biología Molecular, FCEN and IFIBYNE, UBA-CONICET, Buenos Aires, Argentina. The ultraviolet (UV) radiation from the Sun that reaches the Earth?s surface is a combination of low (UVA, 320-400nm) and high (UVB, 290-320nm) energy light. UVB light causes two types of mutagenic DNA lesions: thymine dimers and (6-4)photo-products. UVB mutagenesis is a critical step in the generation of different forms of skin cancer, which develops almost exclusively in sun exposed areas. We have previously shown that RNA polymerase II (pol II) hyperphosphorylation induced by UVC (254 nm) irradiation of non-skin cells inhibits pol II elongation rates which in turn affects alternative splicing (AS) patterns altering the synthesis of pro- and anti-apoptotic isoforms of key proteins like Bcl-x or Caspase 9 (C9). Since the UVC radiation is fully filtered by the ozone layer and AS regulation in skin pathologies has been poorly studied, we decided to extend our studies to human keratinocytes in culture treated with UVB (302nm) light. We observed that pol II hyperphosphorylation is increased being this modification necessary for the observed change in AS of a model cassette exon. Moreover, UVB irradiation induces the pro-apoptotic mRNA isoforms of Bcl-x and C9 being these results consistent with a key role of AS in skin response to DNA damage. Our results suggest that UVB light affects alternative splicing decisions through a mechanism similar to the one we have previously described for UVC light. This indicates that low energy irradiation causing more limited DNA damage than UVC light is sufficient to alter qualitatively patterns of gene expression in skin cells.