CDKL5 kinase controls transcription-coupled responses to DNA damage

Taran Khanam, Ivan Muñoz, Florian Weiland, Thomas Carroll, Michael Morgan, Barbara N. Borsos, Vasiliki Pantazi, Meghan Slean, Miroslav Novak, Rachel Toth, Paul Appleton, Tibor Pankotai, Houjiang Zhou, John Rouse

Research output: Contribution to journalArticlepeer-review

10 Scopus citations


Mutations 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.
Original languageEnglish (US)
StatePublished - Oct 4 2021

Bibliographical note

KAUST Repository Item: Exported on 2021-10-11
Acknowledgements: We 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

ASJC Scopus subject areas

  • General Neuroscience
  • General Biochemistry, Genetics and Molecular Biology
  • Molecular Biology
  • General Immunology and Microbiology


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