A molecular mechanism for the "digital" response of p53 to stress.
DNA twist flexibility
gene-expression regulation
p53
protein/DNA interactions
Journal
Proceedings of the National Academy of Sciences of the United States of America
ISSN: 1091-6490
Titre abrégé: Proc Natl Acad Sci U S A
Pays: United States
ID NLM: 7505876
Informations de publication
Date de publication:
05 Dec 2023
05 Dec 2023
Historique:
pmc-release:
28
05
2024
medline:
30
11
2023
pubmed:
28
11
2023
entrez:
28
11
2023
Statut:
ppublish
Résumé
The tumor suppressor protein p53 accumulates in response to cellular stress and consequently orchestrates the expression of multiple genes in a p53-level and time-dependent manner to overcome stress consequences, for which a molecular mechanism is currently unknown. Previously, we reported that DNA torsional flexibility distinguishes among p53 response elements (REs) and that transactivation at basal p53 levels is correlated with p53 REs flexibility. Here, we calculated the flexibility of ~200 p53 REs. By connecting functional outcomes of p53-target genes' activation to the calculated flexibility of their REs, we show that genes known to belong to pathways that are activated rapidly upon stress contain REs that are significantly more flexible relative to REs of genes known to be involved in pathways that are activated later in the response to stress. The global structural properties of several p53 REs belonging to different pathways were experimentally validated. Additionally, reporter-gene expression driven by flexible p53 REs occurred at lower p53 levels and with faster rates than expression from rigid REs. Furthermore, analysis of published endogenous mRNA levels of p53-target genes as a function of REs' flexibility showed that early versus late genes differ significantly in their flexibility properties of their REs and that highly flexible p53 REs enable high-activation level exclusively to early-response genes. Overall, we demonstrate that DNA flexibility of p53 REs contributes significantly to functional selectivity in the p53 system by facilitating the initial steps of p53-dependent target-genes expression, thereby contributing to survival versus death decisions in the p53 system.
Identifiants
pubmed: 38015851
doi: 10.1073/pnas.2305713120
pmc: PMC10710088
doi:
Substances chimiques
Tumor Suppressor Protein p53
0
DNA
9007-49-2
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e2305713120Subventions
Organisme : Israel Science Foundation (ISF)
ID : #1517/14
Organisme : Israel Science Foundation (ISF)
ID : #875/22
Déclaration de conflit d'intérêts
Competing interests statement:The authors declare no competing interest.
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