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dc.contributor.authorKhanam, Taran
dc.contributor.authorMuñoz, Ivan
dc.contributor.authorWeiland, Florian
dc.contributor.authorCarroll, Thomas
dc.contributor.authorMorgan, Michael
dc.contributor.authorBorsos, Barbara N.
dc.contributor.authorPantazi, Vasiliki
dc.contributor.authorSlean, Meghan
dc.contributor.authorNovak, Miroslav
dc.contributor.authorToth, Rachel
dc.contributor.authorAppleton, Paul
dc.contributor.authorPankotai, Tibor
dc.contributor.authorZhou, Houjiang
dc.contributor.authorRouse, John
dc.date.accessioned2021-10-10T08:38:43Z
dc.date.available2021-10-10T08:38:43Z
dc.date.issued2021-10-04
dc.date.submitted2021-03-16
dc.identifier.citationKhanam, T., Muñoz, I., Weiland, F., Carroll, T., Morgan, M., Borsos, B. N., … Rouse, J. (2021). CDKL5 kinase controls transcription-coupled responses to DNA damage. The EMBO Journal. doi:10.15252/embj.2021108271
dc.identifier.issn1460-2075
dc.identifier.issn0261-4189
dc.identifier.doi10.15252/embj.2021108271
dc.identifier.urihttp://hdl.handle.net/10754/672464
dc.description.abstractMutations in the gene encoding the CDKL5 kinase are among the most common genetic causes of childhood epilepsy and can also give rise to the severe neurodevelopmental condition CDD (CDKL5 deficiency disorder). Despite its importance for human health, the phosphorylation targets and cellular roles of CDKL5 are poorly understood, especially in the cell nucleus. Here, we report that CDKL5 is recruited to sites of DNA damage in actively transcribed regions of the nucleus. A quantitative phosphoproteomic screen for nuclear CDKL5 substrates reveals a network of transcriptional regulators including Elongin A (ELOA), phosphorylated on a specific CDKL5 consensus motif. Recruitment of CDKL5 and ELOA to damaged DNA, and subsequent phosphorylation of ELOA, requires both active transcription and the synthesis of poly(ADP-ribose) (PAR), to which CDKL5 can bind. Critically, CDKL5 kinase activity is essential for the transcriptional silencing of genes induced by DNA double-strand breaks. Thus, CDKL5 is a DNA damage-sensing, PAR-controlled transcriptional modulator, a finding with implications for understanding the molecular basis of CDKL5-related diseases.
dc.description.sponsorshipWe thank the technical support of the MRC-PPU including the DNA Sequencing Service, Tissue Culture team, Reagents and Services team, and the PPU Mass-Spectrometry team. We also thank Fiona Brown and James Hastie for ELOA phospho-Ser antibody production and purification. We are grateful to Jessica Downs, Simon Boulton and Roger Greenberg for the U-2-OS cells harbouring the FokI silencing reporter and to Nick Lakin for -disrupted U-2-OS cells. We are grateful to Graeme Ball for help with microscopy data analysis. We thank Luis Sanchez-Pulido and Chis Ponting for help with bioinformatics analyses. We thank Petr Walczysko and William Moore for their generous help with generating OMERO figures. We are grateful to members of the Rouse laboratory for useful discussions. BBN and TP were funded by the National Research, Development and Innovation Office grant GINOP-2.2.1-15-2017-00052, EFOP 3.6.3-VEKOP-16-2017-00009, NKFI-FK 132080, the János Bolyai Research Scholarship of the Hungarian Academy of Sciences BO/27/20, UNKP-20-5-SZTE-265, EMBO short-term fellowship 8513 and the Tempus Foundation. This work was supported by the Medical Research Council (grant number: MC_UU_12016/1; TK, IM, JR) and the pharmaceutical companies supporting the Division of Signal Transduction Therapy Unit (Boehringer Ingelheim, GlaxoSmithKline and Merck KGaA). 311 PARP
dc.publisherEMBO
dc.relation.urlhttps://onlinelibrary.wiley.com/doi/10.15252/embj.2021108271
dc.rightsThis is an open access article under theterms of the Creative Commons Attribution License,which permits use, distribution and reproduction inany medium, provided the original work is properlycited.
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.titleCDKL5 kinase controls transcription-coupled responses to DNA damage
dc.typeArticle
dc.contributor.departmentBioscience Core Lab
dc.contributor.departmentProteomics, protein expression & cytomet
dc.identifier.journalThe EMBO Journal
dc.eprint.versionPublisher's Version/PDF
dc.contributor.institutionMRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee, UK
dc.contributor.institutionDepartment of Microbial and Molecular Systems (M²S), Centre for Food and Microbial Technology (CLMT), Laboratory of Enzyme, Fermentation and Brewing Technology (EFBT), Technology Campus Ghent, KU Leuven, Ghent, Belgium
dc.contributor.institutionDepartment of Biochemistry and Biophysics, University of California, San Francisco, CA, USA
dc.contributor.institutionAlbert Szent-Györgyi Medical School, Institute of Pathology, University of Szeged, Szeged, Hungary
dc.contributor.institutionDepartment of Medical Genetics, National Health Service, Polwarth Building, Foresterhill, UK
dc.contributor.institutionJacqui Wood Cancer Centre, Ninewells Hospital, University of Dundee, Dundee, UK
dc.contributor.institutionMRC Reagents and Services, School of Life Sciences, University of Dundee, Dundee, UK
dc.contributor.institutionDundee Imaging Facility, School of Life Sciences, University of Dundee, Dundee, UK
kaust.personZhou, Houjiang
dc.date.accepted2021-09-09
dc.identifier.eid2-s2.0-85116117426
refterms.dateFOA2021-10-10T08:40:57Z


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This is an open access article under theterms of the Creative Commons Attribution License,which permits use, distribution and reproduction inany medium, provided the original work is properlycited.
Except where otherwise noted, this item's license is described as This is an open access article under theterms of the Creative Commons Attribution License,which permits use, distribution and reproduction inany medium, provided the original work is properlycited.