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The core spliceosome as target and effector of non-canonical ATM signalling
Open accessAbstract
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.
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“If replication forks or transcription complexes encounter polymerase-blocking lesions (Vermeij et al., 2016), this can lead to the formation of a DSB or R-loop (Tresini et al., 2015), which potently activate signaling events that halt cell cycle progression and promote repair.”
From DNA damage-how and why we age? (2021) · cites this paper as Tresini et al., 2015
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Citations
Cites
1 retracted
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Metadata
- Authors
- Tresini, M., Warmerdam, D. O., Kolovos, P., Snijder, L., Vrouwe, M. G., Demmers, J. A. A., van IJcken, W. F. J., Grosveld, F. G., Medema, R. H., Hoeijmakers, J. H. J., Mullenders, L. H. F., Vermeulen, W., & Marteijn, J. A.
- Affiliations
- Erasmus MC (NL)
- The Netherlands Cancer Institute (NL)
- Leiden University Medical Center (NL)
- Corresponding author
- Tresini, Maria
- Vermeulen, Wim
- Marteijn, Jurgen A.
- ORCID
- Venue
- Nature
- Published
- 2015-06-24
- Volume
- 523
- Issue
- 7558
- Pages
- 53-58
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4501432
- OpenAlex
- W1823908009
- Cited by
- 252
- References
- 45
- Citations by year
- 2026: 8 · 2025: 13 · 2024: 22 · 2023: 21 · 2022: 22 · 2021: 20 · 2020: 24 · 2019: 25 · 2018: 27 · 2017: 31 · 2016: 25 · 2015: 14
- FWCI
- 14.03
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
- PubMed Central (acceptedVersion)
- Pure Amsterdam UMC (submittedVersion, cc-by)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Leiden Repository (Leiden University) (submittedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- RePub (Erasmus University Rotterdam) (submittedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion)
- Funders
- ZonMw (912.12.132, 912.08.031, 854.11.002)
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek (935.11.042, 823.02.013, 854.11.002, 912.12.132, 912.08.031)
- National Institute on Aging (P01AG017242)
- FP7 Ideas: European Research Council (340988, 233424)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- ATM kinase, alternative splicing, DNA damage response, R-loops, U2 snRNP, U5 snRNP, UV irradiation, RNA polymerase pausing, feed-forward loop, nascent RNA
- MeSH terms
- Cell Line, Chromatin, DNA Damage, Enzyme Activation, Humans, DNA-Directed RNA Polymerases, Ultraviolet Rays, Signal Transduction, Spliceosomes, Alternative Splicing, Ataxia Telangiectasia Mutated Proteins
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