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

Fernando Rodríguez Pérez (), Dean Natwick, Lauren Schiff, David McSwiggen, Alec Heckert, Melina Huey, Huntly Morrison, Mandy Loo, Rafael G. Miranda, John Filbin, Jose Ortega, Kayla Buren, Danny Murnock, Arnold Tao, Renee Butler, Kylie Cheng, William Tarvestad, Zhengjian Zhang, Eric Gonzalez, Rand M. Miller, Marcus Kelly, Yangzhong Tang, Jaclyn Ho, Daniel Anderson, Charlene Bashore and Stephen Basham ()
Additional contact information
Fernando Rodríguez Pérez: Eikon Therapeutics
Dean Natwick: Eikon Therapeutics
Lauren Schiff: Eikon Therapeutics
David McSwiggen: Eikon Therapeutics
Alec Heckert: Eikon Therapeutics
Melina Huey: Eikon Therapeutics
Huntly Morrison: Eikon Therapeutics
Mandy Loo: Eikon Therapeutics
Rafael G. Miranda: Eikon Therapeutics
John Filbin: Eikon Therapeutics
Jose Ortega: Eikon Therapeutics
Kayla Buren: Eikon Therapeutics
Danny Murnock: Eikon Therapeutics
Arnold Tao: Eikon Therapeutics
Renee Butler: Eikon Therapeutics
Kylie Cheng: Eikon Therapeutics
William Tarvestad: Eikon Therapeutics
Zhengjian Zhang: Eikon Therapeutics
Eric Gonzalez: Eikon Therapeutics
Rand M. Miller: Eikon Therapeutics
Marcus Kelly: Eikon Therapeutics
Yangzhong Tang: Eikon Therapeutics
Jaclyn Ho: Eikon Therapeutics
Daniel Anderson: Eikon Therapeutics
Charlene Bashore: Eikon Therapeutics
Stephen Basham: Eikon Therapeutics

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-50178-3

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