Optimisation of TP53 reporters by systematic dissection of synthetic TP53 response elements.
Journal
Nucleic acids research
ISSN: 1362-4962
Titre abrégé: Nucleic Acids Res
Pays: England
ID NLM: 0411011
Informations de publication
Date de publication:
13 Oct 2023
13 Oct 2023
Historique:
accepted:
22
08
2023
revised:
24
07
2023
received:
23
02
2023
pubmed:
31
8
2023
medline:
31
8
2023
entrez:
31
8
2023
Statut:
ppublish
Résumé
TP53 is a transcription factor that controls multiple cellular processes, including cell cycle arrest, DNA repair and apoptosis. The relation between TP53 binding site architecture and transcriptional output is still not fully understood. Here, we systematically examined in three different cell lines the effects of binding site affinity and copy number on TP53-dependent transcriptional output, and also probed the impact of spacer length and sequence between adjacent binding sites, and of core promoter identity. Paradoxically, we found that high-affinity TP53 binding sites are less potent than medium-affinity sites. TP53 achieves supra-additive transcriptional activation through optimally spaced adjacent binding sites, suggesting a cooperative mechanism. Optimally spaced adjacent binding sites have a ∼10-bp periodicity, suggesting a role for spatial orientation along the DNA double helix. We leveraged these insights to construct a log-linear model that explains activity from sequence features, and to identify new highly active and sensitive TP53 reporters.
Identifiants
pubmed: 37650627
pii: 7256891
doi: 10.1093/nar/gkad718
pmc: PMC10570033
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
9690-9702Subventions
Organisme : NIMH NIH HHS
ID : R01 MH106842
Pays : United States
Organisme : NIH HHS
ID : R01MH106842
Pays : United States
Informations de copyright
© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.
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