PRMT1 inhibition perturbs RNA metabolism and induces DNA damage in clear cell renal cell carcinoma

Joseph Walton, Angel S. N. Ng, Karen Arevalo, Anthony Apostoli, Jalna Meens, Christina Karamboulas, Jonathan St-Germain, Panagiotis Prinos, Julia Dmytryshyn, Eric Chen, Cheryl H. Arrowsmith, Brian Raught and Laurie Ailles ()
Additional contact information
Joseph Walton: University of Toronto
Angel S. N. Ng: University of Toronto
Karen Arevalo: University of Toronto
Anthony Apostoli: University Health Network
Jalna Meens: University Health Network
Christina Karamboulas: University Health Network
Jonathan St-Germain: University Health Network
Panagiotis Prinos: University of Toronto
Julia Dmytryshyn: University Health Network
Eric Chen: University Health Network
Cheryl H. Arrowsmith: University of Toronto
Brian Raught: University of Toronto
Laurie Ailles: University of Toronto

Nature Communications, 2024, vol. 15, issue 1, 1-21

Abstract: Abstract In addition to the ubiquitous loss of the VHL gene in clear cell renal cell carcinoma (ccRCC), co-deletions of chromatin-regulating genes are common drivers of tumorigenesis, suggesting potential vulnerability to epigenetic manipulation. A library of chemical probes targeting a spectrum of epigenetic regulators is screened using a panel of ccRCC models. MS023, a type I protein arginine methyltransferase (PRMT) inhibitor, is identified as an antitumorigenic agent. Individual knockdowns indicate PRMT1 as the specific critical dependency for cancer growth. Further analyses demonstrate impairments to cell cycle and DNA damage repair pathways upon MS023 treatment or PRMT1 knockdown. PRMT1-specific proteomics reveals an interactome rich in RNA binding proteins and further investigation indicates significant widespread disruptions in mRNA metabolism with both MS023 treatment and PRMT1 knockdown, resulting in R-loop accumulation and DNA damage over time. Our data supports PRMT1 as a target in ccRCC and informs a mechanism-based strategy for translational development.

Date: 2024
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DOI: 10.1038/s41467-024-52507-y

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