WRN inhibition leads to its chromatin-associated degradation via the PIAS4-RNF4-p97/VCP axis.

Werner Syndrome Helicase / metabolism Humans Animals Chromatin / metabolism Valosin Containing Protein / metabolism Protein Inhibitors of Activated STAT / metabolism Mice Cell Line, Tumor Nuclear Proteins / metabolism Microsatellite Instability Proteolysis / drug effects Sumoylation / drug effects Transcription Factors / metabolism Xenograft Model Antitumor Assays Female

Journal

Nature communications

ISSN: 2041-1723

Titre abrégé: Nat Commun

Pays: England

ID NLM: 101528555

Informations de publication

Date de publication:
18 Jul 2024

Historique:

received: 19 12 2023

accepted: 01 07 2024

medline: 19 7 2024

pubmed: 19 7 2024

entrez: 18 7 2024

Statut: epublish

Résumé

Synthetic lethality provides an attractive strategy for developing targeted cancer therapies. For example, cancer cells with high levels of microsatellite instability (MSI-H) are dependent on the Werner (WRN) helicase for survival. However, the mechanisms that regulate WRN spatiotemporal dynamics remain poorly understood. Here, we used single-molecule tracking (SMT) in combination with a WRN inhibitor to examine WRN dynamics within the nuclei of living cancer cells. WRN inhibition traps the helicase on chromatin, requiring p97/VCP for extraction and proteasomal degradation in a MSI-H dependent manner. Using a phenotypic screen, we identify the PIAS4-RNF4 axis as the pathway responsible for WRN degradation. Finally, we show that co-inhibition of WRN and SUMOylation has an additive toxic effect in MSI-H cells and confirm the in vivo activity of WRN inhibition using an MSI-H mouse xenograft model. This work elucidates a regulatory mechanism for WRN that may facilitate identification of new therapeutic modalities, and highlights the use of SMT as a tool for drug discovery and mechanism-of-action studies.

Identifiants

DOI: 10.1038/s41467-024-50178-3 PMID: 39025847

pubmed: 39025847

doi: 10.1038/s41467-024-50178-3

pii: 10.1038/s41467-024-50178-3

doi:

Substances chimiques

Werner Syndrome Helicase EC 3.6.4.12

WRN protein, human EC 3.6.4.12

Chromatin 0

Valosin Containing Protein EC 3.6.4.6

Protein Inhibitors of Activated STAT 0

VCP protein, human EC 3.6.4.6

Nuclear Proteins 0

Transcription Factors 0

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

Pagination

6059

Informations de copyright

Références

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