GLYCOGEN SYNTHASE KINASE 3 PLAYS A CENTRAL ROLE IN THE TRANSCRIPTIONAL RESPONSE TO UV-INDUCED DNA DAMAGE

SORIA, GASTÓN; VILLAFAÑEZ, FLORENCIA; KORNBLIHTT, A.R.; NIETO MORENO, N.; MUÑOZ, M.J.

Salta

Conferencia; Joint LV Annual SAIB Meeting and XIV PABMB Congress; 2019

SAIB PABMB

DNA integrity is a major requisite for life and therefore cells develop a concerted response upon DNA damage. At the gene expression level, thisresponse consists of a genome wide downregulation of transcription initiation and elongation rates, as well as the modulation of alternativesplicing (AS) patterns. In particular, we have described that UV-induced DNA lesions trigger an in trans signaling cascade that promoteshyperphosphorylation of the carboxyl-terminal domain (CTD) of RNA polymerase II (RNAPII), a decrease in transcription elongation rates andchanges in AS patterns in the context of the kinetic coupling model between transcription and splicing.In order to identify kinases mediating this response, we performed a screening with the Public Kinase Inhibitors Library (PKIS2) fromGlaxoSmithKline and identified glycogen synthase kinase 3 (GSK-3) as a central player: GSK-3 inhibition prevents UV-induced RNAPIIhyperphosphorylation, as well as the changes in AS patterns and the decrease in transcription elongation rates. Using RNAPII ChIP analysis wedetected that while intragenic RNAPII occupancy is increased upon UV irradiation, consistent with a decrease in RNAPII elongation rates,GSK-3 inhibition prevents this increase. In addition, GSK-3 inhibition prevents UV-induced apoptosis. Finally, since RNAPII CTD adjusts tothe GSK-3 consensus site, and it was reported that GSK-3 translocates to the nucleus in stress conditions, we are currently testing the hypothesisthat GSK-3 may be phosphorylating RNAPII in a direct manner. Altogether, our results set GSK-3 as a central kinase in the transcriptionalresponse to DNA damage.