Assistant Professor, Department of Cellular and Molecular Medicine
Work: (613) 562-5800 ext. 8908
A cell’s function is specified by the cohort of proteins that it expresses throughout its life-cycle. These proteins are themselves modified in space and time to dictate localization, structure, and activity. Our group studies the function of a protein modification called acetylation. Acetylation was first characterized as a critical regulator of proteins that bind to DNA (housing all genetic information specifying who we are). Recent work from our group and others suggests that acetylation is more pervasive than ever expected, targeting proteins with diverse biological functions related to cancer, ageing and metabolic syndromes. We aim to identify the function of these modifications and to determine how their regulation can be exploited to diagnose and treat disease.
The Downey Lab accepts graduate students from the Department of Cellular and Molecular Medicine.
Our research focuses on the intersection of the emerging field of non-histone protein acetylation and the regulation of cellular stress responses (both metabolic and genomic). While acetylation machineries have long been known to regulate eukaryotic stress pathways via the acetylation of histone tails at gene promoters, more recent work has demonstrated that these proteins also impact diverse biological pathways, in all kingdoms of life, through the modulation of non-histone targets.
Our most recent work has employed large-scale quantitative mass-spectrometry to decipher how the “acetylome” is regulated by enzymes previously implicated in various aspects of metabolic control and genome stability. While this work began in yeast, we have more recently extended these methods to transformed human cell lines wherein we have identified conserved protein targets for future study.
Our work, which will continue to integrate studies in yeast and mammalian systems, will have important implications for cancer biology, ageing and other aspects of human health. We aim to take creative approaches to delve into poorly understood areas of enzyme regulation and mechanisms of substrate selection. A systems biology perspective will be crucial to understanding acetylation as a global regulator. In particular, our work will provide opportunities for trainees interested in genetics, stress signaling, protein structure and function and high-throughput biology.
Downey M, Johnson JR, Davey NE, Newton BW, Johnson TL, Galaang S, Seller CA, Krogan N, Toczyski DP. Acetylome profiling reveals overlap in the regulation of diverse processes by sirtuins, gcn5, and esa1. Mol Cell Proteomics. 2015 Jan;14(1):162-76. doi: 10.1074/mcp.M114.043141. Epub 2014 Nov 7.
Edenberg ER, Downey M, Toczyski D. Polymerase stalling during replication, transcription and translation. Curr Biol. 2014 May 19;24(10):R445-52. doi: 10.1016/j.cub.2014.03.060.
Downey M, Knight B, Vashisht AA, Seller CA, Wohlschlegel JA, Shore D, Toczyski DP. Gcn5 and sirtuins regulate acetylation of the ribosomal protein transcription factor Ifh1. Curr Biol. 2013 Sep 9;23(17):1638-48. doi: 10.1016/j.cub.2013.06.050. Epub 2013 Aug 22.
Downey M, Edenberg ER, Toczyski DP. Repair scaffolding reaches new heights at blocked replication forks. Mol Cell. 2010 Jul 30;39(2):162-4. doi: 10.1016/j.molcel.2010.07.007.
Mao DY, Neculai D, Downey M, Orlicky S, Haffani YZ, Ceccarelli DF, Ho JS, Szilard RK, Zhang W, Ho CS, Wan L, Fares C, Rumpel S, Kurinov I, Arrowsmith CH, Durocher D, Sicheri F. Atomic structure of the KEOPS complex: an ancient protein kinase-containing molecular machine. Mol Cell. 2008 Oct 24;32(2):259-75. doi: 10.1016/j.molcel.2008.10.002