INVESTIGADORES
KORNBLIHTT Alberto Rodolfo
artículos
Título:
DNA damage regulates alternative splicing through inhibition of RNA polymerase II elongation.
Autor/es:
MUÑOZ, M; 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
Revista:
CELL
Editorial:
CELL PRESS
Referencias:
Año: 2009 p. 708 - 720
ISSN:
0092-8674
Resumen:
DNA damage induces apoptosis and many apoptotic genes are regulated via
alternative splicing (AS), but little is known about the control
mechanisms. Here we show that ultraviolet irradiation (UV) affects
cotranscriptional AS in a p53-independent way, through the
hyperphosphorylation of RNA polymerase II carboxy-terminal domain (CTD)
and a subsequent inhibition of transcriptional elongation, estimated in
vivo and in real time. Phosphomimetic CTD mutants not only display lower
elongation but also duplicate the UV effect on AS. Consistently,
nonphosphorylatable mutants prevent the UV effect. Apoptosis promoted by
UV in cells lacking p53 is prevented when the change in AS of the
apoptotic gene bcl-x is reverted, confirming the relevance of this
mechanism. Splicing-sensitive microarrays revealed a significant overlap
of the subsets of genes that have changed AS with UV and those that
have reduced expression, suggesting that transcriptional coupling to AS
is a key feature of the DNA-damage response.