Abstract A05: The mitochondrial RNA polymerase is an essential downstream effector of the MYC oncoprotein
Authors: Taylor Amanda , Zhang Xiaoyong , Cotney Justin , Shadel Gerald , Cameron Craig , McMahon Steven 
Published: October 2015

Abstract
Much of the metabolic reprogramming seen in cancer cells, known as the Warburg effect, is regulated by the MYC oncoprotein. Among MYC-regulated changes are: addiction to exogenous glutamine and increased transcription of the lactate dehydrogenase-A gene. MYC also regulates expression of the cad gene, which encodes three enzymes in the pyrimidine biosynthesis pathway, as well as other enzymes linked to nucleotide biosynthesis. Another MYC-regulated change is increased mitochondrial biogenesis and mitochondrial genome (mtDNA) content, despite a decrease in ATP generation via the mitochondrial electron transport chain (ETC). Via a screen designed to isolate MYC targets whose transcription is tightly correlated with malignant transformation, the mitochondrial RNA polymerase (POLRMT) gene was identified by our group. POLRMT levels are regulated by MYC in cells from many forms of human cancer, including those from various forms of leukemia, lymphoma, myeloma, melanoma, and epithelial tumors. POLRMT is a nuclear gene that encodes the single-chain polypeptide RNA polymerase responsible for all transcription in the mitochondria. We have demonstrated that MYC controls transcription of the mitochondrial genome via POLRMT. Genetic rescue experiments show that induction of POLRMT is necessary for MYC to cause increased mtDNA content. Remarkably, blocking induction of POLRMT by MYC causes a synthetic lethality whereby the cells undergo apoptosis. This has been accomplished using either RNAi methods or small molecules that selectively inhibit POLRMT. POLRMT function is critical for a number of biochemical pathways in the cell and we have focused on defining which of these explains the strict requirement for POLRMT in the survival of MYC expressing tumor cells. POLRMT has well-characterized roles in Electron Transport Chain (ETC) subunit expression and has recently been shown to interact with the Mitochondrial Transcription Factor B1 (TFB1M) to regulate translation of mitochondrial-encoded genes. In addition, a splice variant of POLRMT has also been shown to transcribe a small subset of genes in the nuclear genome. Our results suggest that the nuclear isoform of POLRMT is not linked to the survival of MYC expressing cells. Among the many mitochondrial events that are disrupted by blocking POLRMT function are ETC integrity (and subsequent decreases in ATP production and increases in ROS levels), and pyrimidine biosynthesis (which relies on ETC-dependent function of the mitochondrial DHODH enzyme). Ultimately, our goal is to understand which of these defects explains the robust apoptosis induced in MYC-expressing cells by POLRMT inhibition.
Citation Format: Amanda Taylor, Xiaoyong Zhang, Justin Cotney, Gerald Shadel, Craig Cameron, Steven McMahon. The mitochondrial RNA polymerase is an essential downstream effector of the MYC oncoprotein. [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr A05.