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Nature. 2015 Jul 2;523(7558):53-8. doi: 10.1038/nature14512. Epub 2015 Jun 24.

The core spliceosome as target and effector of non-canonical ATM signalling.

Author information

1
Department of Genetics, Cancer Genomics Netherlands, Erasmus University Medical Center, Rotterdam, 3015 CN, The Netherlands.
2
Division of Cell Biology, Netherlands Cancer Institute, Amsterdam, 1066 CX, The Netherlands.
3
Department of Cell Biology, Erasmus University Medical Center, Rotterdam, 3015 CN, The Netherlands.
4
Department of Human Genetics, Leiden University Medical Center, Leiden, 2333 ZC, The Netherlands.
5
Erasmus MC Proteomics Center, Erasmus University Medical Center, Rotterdam, 3015 CN, The Netherlands.
6
Erasmus Center for Biomics, Erasmus University Medical Center, Rotterdam, 3015 CN, The Netherlands.

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.

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PMID:
26106861
PMCID:
PMC4501432
DOI:
10.1038/nature14512
[Indexed for MEDLINE]
Free PMC Article
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