title: The core spliceosome as target and effector of non-canonical ATM signalling.
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 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.
authors.affiliation: Department of Genetics, Cancer Genomics Netherlands, Erasmus University Medical Center, Rotterdam, 3015 CN, The Netherlands.
authors.forename: Maria
authors.initials: M
authors.lastname: Tresini
authors.affiliation: Division of Cell Biology, Netherlands Cancer Institute, Amsterdam, 1066 CX, The Netherlands.
authors.forename: Daniël O
authors.initials: DO
authors.lastname: Warmerdam
authors.affiliation: Department of Cell Biology, Erasmus University Medical Center, Rotterdam, 3015 CN, The Netherlands.
authors.forename: Petros
authors.initials: P
authors.lastname: Kolovos
authors.affiliation: Department of Genetics, Cancer Genomics Netherlands, Erasmus University Medical Center, Rotterdam, 3015 CN, The Netherlands.
authors.forename: Loes
authors.initials: L
authors.lastname: Snijder
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Leiden, 2333 ZC, The Netherlands.
authors.forename: Mischa G
authors.initials: MG
authors.lastname: Vrouwe
authors.affiliation: Erasmus MC Proteomics Center, Erasmus University Medical Center, Rotterdam, 3015 CN, The Netherlands.
authors.forename: Jeroen A A
authors.initials: JA
authors.lastname: Demmers
authors.affiliation: Erasmus Center for Biomics, Erasmus University Medical Center, Rotterdam, 3015 CN, The Netherlands.
authors.forename: Wilfred F J
authors.initials: WF
authors.lastname: van IJcken
authors.affiliation: Department of Cell Biology, Erasmus University Medical Center, Rotterdam, 3015 CN, The Netherlands.
authors.forename: Frank G
authors.initials: FG
authors.lastname: Grosveld
authors.affiliation: Division of Cell Biology, Netherlands Cancer Institute, Amsterdam, 1066 CX, The Netherlands.
authors.forename: René H
authors.initials: RH
authors.lastname: Medema
authors.affiliation: Department of Genetics, Cancer Genomics Netherlands, Erasmus University Medical Center, Rotterdam, 3015 CN, The Netherlands.
authors.forename: Jan H J
authors.initials: JH
authors.lastname: Hoeijmakers
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Leiden, 2333 ZC, The Netherlands.
authors.forename: Leon H F
authors.initials: LH
authors.lastname: Mullenders
authors.affiliation: Department of Genetics, Cancer Genomics Netherlands, Erasmus University Medical Center, Rotterdam, 3015 CN, The Netherlands.
authors.forename: Wim
authors.initials: W
authors.lastname: Vermeulen
authors.affiliation: Department of Genetics, Cancer Genomics Netherlands, Erasmus University Medical Center, Rotterdam, 3015 CN, The Netherlands.
authors.forename: Jurgen A
authors.initials: JA
authors.lastname: Marteijn
mesh_terms: D017398:Alternative Splicing / Q000502:physiology; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism*; D002460:Cell Line; D002843:Chromatin / Q000378:metabolism; D004249:DNA Damage / Q000502:physiology*; D012321:DNA-Directed RNA Polymerases / Q000378:metabolism; D004789:Enzyme Activation; D006801:Humans; D015398:Signal Transduction; D017381:Spliceosomes / Q000378:metabolism*; D014466:Ultraviolet Rays
chemical_list: D002843:Chromatin; D064007:Ataxia Telangiectasia Mutated Proteins; D012321:DNA-Directed RNA Polymerases