TY - JOUR
T1 - The core spliceosome as target and effector of non-canonical ATM signalling
AU - Tresini, Maria
AU - Warmerdam, Daniël O.
AU - Kolovos, Petros
AU - Snijder, Loes
AU - Vrouwe, Mischa G.
AU - Demmers, Jeroen A.A.
AU - Van Ijcken, Wilfred F.J.
AU - Grosveld, Frank G.
AU - Medema, René H.
AU - Hoeijmakers, Jan H.J.
AU - Mullenders, Leon H.F.
AU - Vermeulen, Wim
AU - Marteijn, Jurgen A.
N1 - Publisher Copyright:
© 2015 Macmillan Publishers Limited. All rights reserved.
PY - 2015/7/1
Y1 - 2015/7/1
N2 - 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 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.
AB - 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 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.
UR - http://www.scopus.com/inward/record.url?scp=84962385367&partnerID=8YFLogxK
U2 - 10.1038/nature14512
DO - 10.1038/nature14512
M3 - Article
C2 - 26106861
AN - SCOPUS:84962385367
SN - 0028-0836
VL - 523
SP - 53
EP - 58
JO - Nature
JF - Nature
IS - 7558
ER -