Abstract
Mutation of the CDKL5 kinase gene leads to the seizure-prone neurodevelopmental condition CDD (CDKL5 deficiency disorder) and is the most common genetic cause of childhood epilepsy. However, the phospho-targets and roles of CDKL5 are poorly understood, especially in the nucleus. We reveal CDKL5 as a sensor of DNA damage in actively transcribed regions of the nucleus, which phosphorylates transcriptional regulators such as Elongin A (ELOA) on a specific consensus motif. Recruitment of CDKL5 and ELOA to DNA damage sites, and subsequent ELOA phosphorylation, requires both active transcription and synthesis of poly–ADP ribose to which CDKL5 can bind. Critically, CDKL5 is essential for transcriptional control at DNA breaks. Therefore, CDKL5 is a DNA damage-sensing regulator of transcription, with implications for CDKL5-related human diseases.
One sentence summary CDKL5 kinase phosphorylates transcriptional regulators and modulates the activity of damaged transcriptional units
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
Author affiliations updated and ORCID included for all the authors. Middle name 'N' added for the author Barbara Borsos.It is now Barbara N Borsos Supplemental files updated with added references. There are now 30 references in the revised version A url added for Validation TMT https://doi.org/10.5281/zenodo.4311494