GLYCOGEN SYNTHASE KINASE 3 INHIBITION PREVENTS UV ELICITED TRANSCRIPTIONAL RESPONSE AND APOPTOSIS

CUENCA, C.; MUÑOZ, M.J.; NIETO MORENO, N.; SORIA, G.; VILLAFÁÑEZ, F.; KORNBLIHTT, A.R.

Paraná

Congreso; 54th Reunión Anual Sociedad Argentina de Investigación en Bioquímica y Biología Molecular; 2018

Sociedad Argentina de Investigación en Bioquímica y Biología Molecular

UV irradiation induced DNA lesions trigger a transcriptional response that includes RNAPII hyperphosphorylation, a decrease in RNAPIIelongation rate and changes in gene expression, including changes in alternative splicing patterns that lead to apoptosis. We recently describedthat UV induced cyclobutane pyrimidine dimers (CPDs) trigger a signal transduction cascade, mediated by ATR that ends in the abovementioned transcriptional response. To unveil other kinases involved in this cascade, we developed an alternative splicing fluorescent reportersystem that allowed us to perform a screening with the Public Kinase Inhibitors Library (PKIS2) from GlaxoSmithKline. From the almost 700inhibitors screened, 12 resulted to affect the UV induced transcriptional response and glycogen synthase kinase 3 (GSK-3) came out as the mostprominent common target. Further validation of the role of GSK-3 was obtained with the highly-specific commercial GSK-3 inhibitors ARA014418 and CHIR 99021. We found that GSK-3 inhibition prevents RNAPII hyperphosphorylation as well as the decrease in RNAPIIelongation rate, the changes in alternative splicing patterns and apoptosis. Altogether, our results indicate an essential role for GSK-3 in the UVinduced transcriptional response.