Publication Date:
2015-06-25
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4501432/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4501432/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tresini, Maria -- Warmerdam, Daniel O -- Kolovos, Petros -- Snijder, Loes -- Vrouwe, Mischa G -- Demmers, Jeroen A A -- van IJcken, Wilfred F J -- Grosveld, Frank G -- Medema, Rene H -- Hoeijmakers, Jan H J -- Mullenders, Leon H F -- Vermeulen, Wim -- Marteijn, Jurgen A -- 10-0594/Worldwide Cancer Research/United Kingdom -- 233424/European Research Council/International -- 340988/European Research Council/International -- P01 AG017242/AG/NIA NIH HHS/ -- England -- Nature. 2015 Jul 2;523(7558):53-8. doi: 10.1038/nature14512. Epub 2015 Jun 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Genetics, Cancer Genomics Netherlands, Erasmus University Medical Center, Rotterdam, 3015 CN, The Netherlands. ; Division of Cell Biology, Netherlands Cancer Institute, Amsterdam, 1066 CX, The Netherlands. ; Department of Cell Biology, Erasmus University Medical Center, Rotterdam, 3015 CN, The Netherlands. ; Department of Human Genetics, Leiden University Medical Center, Leiden, 2333 ZC, The Netherlands. ; Erasmus MC Proteomics Center, Erasmus University Medical Center, Rotterdam, 3015 CN, The Netherlands. ; Erasmus Center for Biomics, Erasmus University Medical Center, Rotterdam, 3015 CN, The Netherlands.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26106861" target="_blank"〉PubMed〈/a〉
Keywords:
Alternative Splicing/physiology
;
Ataxia Telangiectasia Mutated Proteins/*metabolism
;
Cell Line
;
Chromatin/metabolism
;
DNA Damage/*physiology
;
DNA-Directed RNA Polymerases/metabolism
;
Enzyme Activation
;
Humans
;
*Signal Transduction
;
Spliceosomes/*metabolism
;
Ultraviolet Rays
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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