The core spliceosome as target and effector of non-canonical ATM signalling
Tresini, Maria; Warmerdam, Daniël O; Kolovos, Petros; Snijder, Loes; Vrouwe, Mischa G; Demmers, Jeroen A A; van IJcken, Wilfred F J; Grosveld, Frank G; Medema, René H; Hoeijmakers, Jan H J; Mullenders, Leon H F; Vermeulen, Wim; Marteijn, Jurgen A
(2015) Nature, volume 523, issue 7558, pp. 53 - 58
(Article)
Abstract
In response to DNA damage, tissue homoeostasis is ensured by protein networks promoting DNA repair, cell cycle arrest or apoptosis. DNA damage response signalling pathways coordinate these processes, partly by propagating gene-expression-modulating signals. DNA damage influences not only the abundance of messenger RNAs, but also their coding information through alternative
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splicing. Here we show that transcription-blocking DNA lesions promote chromatin displacement of late-stage spliceosomes and initiate a positive feedback loop centred on the signalling kinase ATM. We propose that initial spliceosome displacement and subsequent R-loop formation is triggered by pausing of RNA polymerase at DNA lesions. In turn, R-loops activate ATM, which signals to impede spliceosome organization further and augment ultraviolet-irradiation-triggered alternative splicing at the genome-wide level. Our findings define R-loop-dependent ATM activation by transcription-blocking lesions as an important event in the DNA damage response of non-replicating cells, and highlight a key role for spliceosome displacement in this process.
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Keywords: Alternative Splicing, Ataxia Telangiectasia Mutated Proteins, Cell Line, Chromatin, DNA Damage, DNA-Directed RNA Polymerases, Enzyme Activation, Humans, Signal Transduction, Spliceosomes, Ultraviolet Rays, Journal Article, Research Support, Non-U.S. Gov't
ISSN: 0028-0836
Publisher: Nature Publishing Group
(Peer reviewed)