RNA Polymerase III Transcription in Health and Disease

Ian Willis

Our laboratory studies gene transcription by RNA polymerase (Pol) III and the functional impact of this system on normal and disease processes. The products of Pol III transcription are small non-coding RNAs that have diverse and expanding functions in eukaryotic cells. These include RNAs that are central players in cell growth, with roles in protein synthesis, and molecules that function in RNA processing, protein secretion and in various regulatory capacities. Proper regulation of Pol III transcription is critical for balanced growth and its deregulation is a key event in cell transformation and tumorigenesis. For these reasons, much of our research has focused on the Maf1 protein, a master negative regulator of Pol III transcription, and its regulation by nutrient- and stress-signaling pathways that control ribosome and tRNA synthesis. Our programs span genetics, molecular biology, biochemistry, metabolism and structural biology and utilize budding yeast and mice as model experimental systems. Two important areas of concentration are highlighted below.

Mechanisms of Obesity Resistance in Maf1 Knockout Mice
Mice with a whole body knockout of Maf1 are resistant to diet-induced obesity and have increased healthspan. Obesity resistance in these mice is associated with increased energy expenditure and metabolic inefficiency. Our current mechanistic understanding of these phenotypes is based on a novel futile RNA cycle hypothesis wherein deregulated Pol III transcription serves as an energy sink, consuming energetically costly nucleotides in the wasteful synthesis of RNA that does not accumulate and is mostly degraded. Current research on this unique model is focused on understanding global (whole body) and cell-specific molecular and metabolic changes that enhance energy expenditure and contribute to the lean phenotype. We are also exploring the possibility that MAF1 may be targeted therapeutically to treat obesity and improve healthspan.

Mechanisms of Neurodegeneration in Pol III-related Leukodystrophy
Pol III-related leukodystrophy was recently identified as a genetically inherited neurodegenerative disease. The early-onset form of the disease manifests in children as a progressive decline in motor function, cognitive regression and intellectual disability with variable neurological and non-neurological features. We have developed a mouse model of this disease and have characterized numerous behavioral and neuropathological phenotypes. Our research seeks to understand the mechanisms of pathogenesis in different neural cell populations and their molecular basis. The work is currently focused on the oligodendrocyte lineage since hypomyelination is a hallmark of the disease in patients and in the mice.

Selected References

Lee, J., Moir, R.D., McIntosh, K and Willis, I.M. (2012) TOR Signalling Regulates Ribosome and tRNA Synthesis via LAMMER and GSK-3 Family Kinases. Mol. Cell. 45, 836-843.

Moir, R.D and Willis, I.M. (2013) Regulation of Pol III Transcription by Nutrient and Stress Signaling Pathways. Biochim. Biophys. Acta 1829, 361-375.

Sanchez-Casalongue ME, Lee J, Diamond A, Shuldiner S, et al., (2015) Differential Phosphorylation of a Regulatory Subunit of Protein Kinase CK2 by TOR Complex 1 Signaling and the Cdc-like Kinase Kns1. J Biol Chem. 290, 7221-7233

Lee J, Moir RD and Willis IM. (2015) Differential Phosphorylation of RNA Polymerase III and the Initiation Factor TFIIIB in Saccharomyces cerevisiae. PLoS One 10, e0127225.

Bonhoure N, Byrnes A, Moir RD, Hodroj W, et al., (2015) Loss of the RNA Polymerase III Repressor MAF1 Confers Obesity Resistance. Genes & Dev. 29, 934-947.

Willis IM and Moir RD. (2018) Signaling to and from the RNA polymerase III Transcription and Processing Machinery. Ann. Rev. Biochem. 87, 75-100.

Willis IM, Moir RD and Hernandez, N. (2018) Metabolic Programing a Lean Phenotype by Deregulation of RNA Polymerase III. Proc. Natl. Acad. Sci. USA. 115, 12182-12187.

Vorländer MK, Baudin F, Moir RD, Wetzel R, et al., (2020) Structural basis for RNA polymerase III transcription repression by Maf1. Nat. Struct. Mol. Biol. 27, 229-232.

Bonhoure N, Praz V, Moir RD, Willemin G, et al., (2020) MAF1 is a Chronic Repressor of RNA Polymerase III Transcription in the Mouse. Sci. Rep. 10, 11956.