DNA Damage Regulates Alternative Splicing through Inhibition of RNA Polymerase II Elongation

MUÑOZ MJ, PÉREZ SANTANGELO MS, PARONETTO MP, DE LA MATA M, PELISCH F, BOIREAU S, GLOVER-CUTTER K, BEN-DOV C, BLAUSTEIN M, LOZANO JJ, BIRD G, BENTLEY D, BERTRAND E, KORNBLIHTT AR.

CELL

Elsevier

Año: 2009 vol. 137 p. 708 - 720

0092-8674

DNA damage induces apoptosis and many apoptoticgenes are regulated via alternative splicing (AS), butlittle is known about the control mechanisms. Herewe show that ultraviolet irradiation (UV) affectscotranscriptional AS in a p53-independent way,through the hyperphosphorylation of RNA polymeraseII carboxy-terminal domain (CTD) and asubsequent inhibition of transcriptional elongation,estimated in vivo and in real time. PhosphomimeticCTD mutants not only display lower elongation butalso duplicate the UV effect on AS. Consistently, nonphosphorylatablemutants prevent the UV effect.Apoptosis promoted by UV in cells lacking p53 is preventedwhen the change in AS of the apoptotic genebcl-x is reverted, confirming the relevance of thismechanism. Splicing-sensitive microarrays revealeda significant overlap of the subsets of genes thathave changed AS with UV and those that havereduced expression, suggesting that transcriptionalcoupling to AS is a key feature of the DNA-damageresponse.