Structural insights into p300 regulation and acetylation-dependent genome organisation.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
15 12 2022
15 12 2022
Historique:
received:
25
07
2022
accepted:
29
11
2022
entrez:
15
12
2022
pubmed:
16
12
2022
medline:
20
12
2022
Statut:
epublish
Résumé
Histone modifications are deposited by chromatin modifying enzymes and read out by proteins that recognize the modified state. BRD4-NUT is an oncogenic fusion protein of the acetyl lysine reader BRD4 that binds to the acetylase p300 and enables formation of long-range intra- and interchromosomal interactions. We here examine how acetylation reading and writing enable formation of such interactions. We show that NUT contains an acidic transcriptional activation domain that binds to the TAZ2 domain of p300. We use NMR to investigate the structure of the complex and found that the TAZ2 domain has an autoinhibitory role for p300. NUT-TAZ2 interaction or mutations found in cancer that interfere with autoinhibition by TAZ2 allosterically activate p300. p300 activation results in a self-organizing, acetylation-dependent feed-forward reaction that enables long-range interactions by bromodomain multivalent acetyl-lysine binding. We discuss the implications for chromatin organisation, gene regulation and dysregulation in disease.
Identifiants
pubmed: 36522330
doi: 10.1038/s41467-022-35375-2
pii: 10.1038/s41467-022-35375-2
pmc: PMC9755262
doi:
Substances chimiques
Nuclear Proteins
0
Lysine
K3Z4F929H6
Transcription Factors
0
Chromatin
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
7759Subventions
Organisme : Medical Research Council
ID : MR/W001667/1
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 221881/Z/20/Z
Pays : United Kingdom
Organisme : Worldwide Cancer Research
ID : 16-0280
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_PC_17136
Pays : United Kingdom
Organisme : Wellcome Trust
Pays : United Kingdom
Informations de copyright
© 2022. The Author(s).
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