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

Maria Tresini (), Daniël O. Warmerdam, Petros Kolovos, Loes Snijder, Mischa G. Vrouwe, Jeroen A. A. Demmers, Wilfred F. J. van IJcken, Frank G. Grosveld, René H. Medema, Jan H. J. Hoeijmakers, Leon H. F. Mullenders, Wim Vermeulen () and Jurgen A. Marteijn ()
Additional contact information
Maria Tresini: Cancer Genomics Netherlands, Erasmus University Medical Center
Daniël O. Warmerdam: Netherlands Cancer Institute
Petros Kolovos: Erasmus University Medical Center
Loes Snijder: Cancer Genomics Netherlands, Erasmus University Medical Center
Mischa G. Vrouwe: Leiden University Medical Center
Jeroen A. A. Demmers: Erasmus MC Proteomics Center, Erasmus University Medical Center
Wilfred F. J. van IJcken: Erasmus Center for Biomics, Erasmus University Medical Center
Frank G. Grosveld: Erasmus University Medical Center
René H. Medema: Netherlands Cancer Institute
Jan H. J. Hoeijmakers: Cancer Genomics Netherlands, Erasmus University Medical Center
Leon H. F. Mullenders: Leiden University Medical Center
Wim Vermeulen: Cancer Genomics Netherlands, Erasmus University Medical Center
Jurgen A. Marteijn: Cancer Genomics Netherlands, Erasmus University Medical Center

Nature, 2015, vol. 523, issue 7558, 53-58

Abstract: 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.

Date: 2015
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DOI: 10.1038/nature14512

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