Epilepsy kinase CDKL5 is a DNA damage sensor which controls transcriptional activity at DNA breaks
Khanam, T.; Munoz, I.; Weiland, F.; Carroll, T.; Borsos, B.; Pantazi, V.; Slean, M.; Novak, M.; Toth, R.; Appleton, P.; Pankotai, T.; Zhou, H.; Rouse, J.
Show 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 summaryCDKL5 is a DNA damage-sensing kinase that modulates transcriptional activity near DNA breaks.
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