Repurposing the Damage Repair Protein Methyl Guanine Methyl Transferase as a Ligand Inducible Fusion Degron

Murawska, Gosia M. and Vogel, Caspar and Jan, Max and Lu, Xinyan and Schild, Matthias and Slabicki, Mikolaj and Zou, Charles and Zhanybekova, Saule and Manojkumar, Manisha and Petzold, Georg and Kaiser, Peter and Thomä, Nicolas and Ebert, Benjamin and Gillingham, Dennis. (2022) Repurposing the Damage Repair Protein Methyl Guanine Methyl Transferase as a Ligand Inducible Fusion Degron. ACS Chemical Biology.

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Official URL: https://edoc.unibas.ch/86589/

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We successfully repurpose the DNA repair protein methylguanine methyltransferase (MGMT) as an inducible degron for protein fusions. MGMT is a suicide protein that removes alkyl groups from the O; 6; position of guanine (O; 6; G) and is thereafter quickly degraded by the ubiquitin proteasome pathway (UPP). Starting with MGMT pseudosubstrates (benzylguanine and lomeguatrib), we first demonstrate that these lead to potent MGMT depletion while affecting little else in the proteome. We then show that fusion proteins of MGMT undergo rapid UPP-dependent degradation in response to pseudosubstrates. Mechanistic studies confirm the involvement of the UPP, while revealing that at least two E3 ligase classes can degrade MGMT depending on cell-line and expression type (native or ectopic). We also demonstrate the technique's versatility with two clinically relevant examples: degradation of KRAS; G12C; and a chimeric antigen receptor.
Faculties and Departments:05 Faculty of Science > Departement Chemie > Chemie > Organische Chemie (Gillingham)
UniBasel Contributors:Gillingham, Dennis
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:American Chemical Society
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:17 Jan 2022 16:21
Deposited On:17 Jan 2022 16:19

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