Post-translational modification-dependent oligomerization switch in regulation of global transcription and DNA damage repair during genotoxic stress.
Humans
DNA Damage
DNA Repair
Acetylation
Phosphorylation
Histone Deacetylases
/ metabolism
Protein Processing, Post-Translational
Transcription, Genetic
RNA Polymerase II
/ metabolism
Transcription Factor TFIID
/ metabolism
Protein Multimerization
HEK293 Cells
HeLa Cells
Transcriptional Elongation Factors
/ metabolism
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
15 May 2024
15 May 2024
Historique:
received:
18
09
2023
accepted:
02
05
2024
medline:
16
5
2024
pubmed:
16
5
2024
entrez:
15
5
2024
Statut:
epublish
Résumé
Mechanisms of functional cross-talk between global transcriptional repression and efficient DNA damage repair during genotoxic stress are poorly known. In this study, using human AF9 as representative of Super Elongation Complex (SEC) components, we delineate detailed mechanisms of these processes. Mechanistically, we describe that Poly-Serine domain-mediated oligomerization is pre-requisite for AF9 YEATS domain-mediated TFIID interaction-dependent SEC recruitment at the promoter-proximal region for release of paused RNA polymerase II. Interestingly, during genotoxic stress, CaMKII-mediated phosphorylation-dependent nuclear export of AF9-specific deacetylase HDAC5 enhances concomitant PCAF-mediated acetylation of K339 residue. This causes monomerization of AF9 and reduces TFIID interaction for transcriptional downregulation. Furthermore, the K339 acetylation-dependent enhanced AF9-DNA-PKc interaction leads to phosphorylation at S395 residue which reduces AF9-SEC interaction resulting in transcriptional downregulation and efficient repair of DNA damage. After repair, nuclear re-entry of HDAC5 reduces AF9 acetylation and restores its TFIID and SEC interaction to restart transcription.
Identifiants
pubmed: 38750015
doi: 10.1038/s41467-024-48530-8
pii: 10.1038/s41467-024-48530-8
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
4128Subventions
Organisme : DBT India Alliance (Wellcome Trust/DBT India Alliance)
ID : IA/S/22/1/506227
Organisme : Council of Scientific and Industrial Research (CSIR)
ID : P-07
Informations de copyright
© 2024. The Author(s).
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