| Autor: |
Rodríguez Pérez, Fernando, Natwick, Dean, Schiff, Lauren, McSwiggen, David, Heckert, Alec, Huey, Melina, Morrison, Huntly, Loo, Mandy, Miranda, Rafael G., Filbin, John, Ortega, Jose, Van Buren, Kayla, Murnock, Danny, Tao, Arnold, Butler, Renee, Cheng, Kylie, Tarvestad, William, Zhang, Zhengjian, Gonzalez, Eric, Miller, Rand M. |
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| Zdroj: |
Nature Communications; 7/18/2024, Vol. 15 Issue 1, p1-17, 17p |
| Abstrakt: |
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. New optical methods for investigating the activity of small molecules in cells may facilitate development of anticancer therapeutics. Here, the authors use a super-resolution optical platform and single molecule tracking to gain insight into WRN regulation in cancer. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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