CDKL5 kinase controls transcription-coupled responses to DNA damage.
DNA Breaks, Double-Stranded
DNA Damage
Elongin
/ genetics
Epileptic Syndromes
/ genetics
Humans
Mutation
Neurons
/ metabolism
Phosphoproteins
/ genetics
Phosphorylation
Poly Adenosine Diphosphate Ribose
/ metabolism
Protein Serine-Threonine Kinases
/ genetics
Spasms, Infantile
/ genetics
Transcriptional Activation
CDKL5 disorder
DNA damage response
kinase
poly(ADP-ribose)
transcriptional regulation
Journal
The EMBO journal
ISSN: 1460-2075
Titre abrégé: EMBO J
Pays: England
ID NLM: 8208664
Informations de publication
Date de publication:
01 12 2021
01 12 2021
Historique:
revised:
08
09
2021
received:
16
03
2021
accepted:
09
09
2021
pubmed:
5
10
2021
medline:
22
12
2021
entrez:
4
10
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 34605059
doi: 10.15252/embj.2021108271
pmc: PMC8634139
doi:
Substances chimiques
ELOA protein, human
0
Elongin
0
Phosphoproteins
0
Poly Adenosine Diphosphate Ribose
26656-46-2
Protein Serine-Threonine Kinases
EC 2.7.11.1
CDKL5 protein, human
EC 2.7.11.22
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e108271Subventions
Organisme : Medical Research Council
ID : MC_UU_00018/5
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_12016/1
Pays : United Kingdom
Informations de copyright
© 2021 The Authors. Published under the terms of the CC BY 4.0 license.
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