Date of Award

Fall 12-8-2023

Embargo Period

12-7-2023

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biochemistry

College

College of Graduate Studies

First Advisor

Wenjian Gan

Second Advisor

Lauren Ball

Third Advisor

Joseph Delaney

Fourth Advisor

Philip Howe

Sixth Advisor

Samar Hammad

Abstract

PRMT5 (Protein arginine methyltransferase 5) is the predominant type II PRMT that monomethylates and symmetrically dimethylates arginine residues of histone and none- histone proteins to regulate diverse cellular processes. PRMT5 overexpression has been implicated in tumorigenesis and other diseases and has gained trac1on as a poten1al an1tumor target with some of its inhibitors being tested in clinical trials. Despite the well- established an1tumor effect of PRMT5 inhibitors, how the efficacy of these inhibitors is regulated is unexplored. We show in this study that autophagy blockage enhances cellular sensi1vity to PRMT5 inhibitor in triple nega1ve breast cancer cells. Both gene1c deple1on and pharmacological inhibi1on of PRMT5 evoke cytoprotec1ve autophagy. We further establish that PRMT5 suppresses basal autophagy across different breast cancer types. Mechanis1cally, PRMT5 catalyzes monomethyla1on of ULK1 at R532 to suppress its autophagic func1ons. As a result, ULK1 inhibi1on or dele1on blocks PRMT5 deficiency- induced autophagy and sensi1zes cells to PRMT5 inhibitor. Our study iden1fies inducible autophagy as an important determinant of cellular sensi1vity to PRMT5 inhibitor, and also establishes ULK1 as a bonafide substrate of PRMT5 in the autophagy, providing a ra1onale for combining PRMT5 and autophagy inhibitors in cancer therapy.

Rights

Copyright is held by the author. All rights reserved.

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