CDKL5 kinase controls transcription-coupled responses to DNA damage

EMBO J. 2021 Dec 1;40(23):e108271. doi: 10.15252/embj.2021108271. Epub 2021 Oct 4.


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.

Keywords: CDKL5 disorder; DNA damage response; kinase; poly(ADP-ribose); transcriptional regulation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • DNA Breaks, Double-Stranded*
  • DNA Damage*
  • Elongin / genetics
  • Elongin / metabolism*
  • Epileptic Syndromes / genetics
  • Epileptic Syndromes / metabolism
  • Epileptic Syndromes / pathology
  • Humans
  • Mutation
  • Neurons / metabolism
  • Neurons / pathology*
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism*
  • Phosphorylation
  • Poly Adenosine Diphosphate Ribose / metabolism
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism*
  • Spasms, Infantile / genetics
  • Spasms, Infantile / metabolism
  • Spasms, Infantile / pathology
  • Transcriptional Activation*


  • ELOA protein, human
  • Elongin
  • Phosphoproteins
  • Poly Adenosine Diphosphate Ribose
  • Protein Serine-Threonine Kinases
  • CDKL5 protein, human

Supplementary concepts

  • CDKL5 deficiency disorder