Onyeka and Mike review the poorly understand area of PTMs on our favourite acetylation enzymes.
https://journals.asm.org/doi/10.1128/mbio.00390-22
New since preprint: Massive PKA activity downregulation in ppx1 mutants expressing PPK, qPCR analyses, additional mass spec confirmations, polyP analyses and measurements
We were a bit player for this one, and it was kind of Dr. Kim to include us. Learn more about his research program here:
Findings: Polyphosphate causes slow growth via inappropriate activation of a PKA-Msn2/4 pathway
Critical Advance: Determines how a key subunit of a polyphosphate synthesis machine gets to where it needs to go. With a cool link to a rare disease. OISB Paper of the Year for 2021!
Contribution of Review: Summarizes recent work by the Jia lab that identifies a novel PPK inhibitor.
Contribution: First comprehensive review of lysine polyphosphorylation in human cells.
Contribution: A resource for the polyP community focused on enzymology of polyP enzymes in microorganisms.
Critical Advance: A new method for studying the effects of polyP INSIDE of human cells.
Downey M 2021. BBA Gene Regulatory Mechanisms.
Non-histone protein acetylation by the evolutionarily conserved GCN5 and PCAF acetyltransferases
Critical Advance: A comprehensive resource of GCN5 and PCAF substrate targeting across diverse models.
BioRxiv preprint version of Bondy-Chorney et al., 2020. Most of our work is published first on BioRxiv to speed dissemination to the research community.
A broad response to intracellular long-chain polyphosphate in human cells
Proteins required for vacuolar function are targets of lysine polyphosphorylation in yeast
Liam McCarthy, Amanda Bentley-DeSousa, Alix Denoncourt, Yi-Chieh Tseng, Matthew Gabriel, Michael Downey. "Proteins required for vacuolar function are targets of lysine polyphosphorylation in yeast." FEBS letters (2020).
This paper was highlighted as an “Editor’s Choice” article. It was also awarded the OISB MSc Paper of the year for 2019.
Critical Advance: An expanded set of polyphosphorylated proteins in yeast brings new opportunities.
Heart failure drug proscillaridin A targets MYC overexpressing leukemia through global loss of lysine acetylation
Elodie M. Da Costa, Gregory Armaos, Gabrielle McInnes, Annie Beaudry, Gaël Moquin-Beaudry, Virginie Bertrand-Lehouillier, Maxime Caron, Chantal Richer, Pascal St-Onge, Jeffrey R. Johnson, Nevan Krogan, Yuka Sai, Michael Downey, Moutih Rafei, Meaghan Boileau, Kolja Eppert, Ema Flores-Díaz, André Haman, Trang Hoang, Daniel Sinnett, Christian Beauséjour, Serge McGraw and Noël J.-M. Raynal
Contribution: We carried out proteomics work to characterize the impact of a new HAT inhibitor on protein acetylation.
SIRT3 controls brown fat thermogenesis by deacetylation regulation of pathways upstream of UCP1
Rajaa Sebaa, Jeff Johnson. Chantal Pileggi, Michael Norgren, Jian Xuan, Yuka Sai, Qiang Tong, Izabella Krystkowiak, Emma Bondy-Chorney, Norman E.Davey, Nevan Krogan, Michael Downey, Mary-Ellen Harper. Molecular Metabolism. 2019.
Critical Advance: Establishes new connections between mitochondrial metabolism and sirtuins in brown fat.
A synthetic non-histone substrate to study substrate targeting by the Gcn5 HAT and sirtuin HDACs
Rössl, A., Denoncourt, A., Lin, M. S., & Downey, M. (2019). A synthetic non-histone substrate to study substrate targeting by the Gcn5 HAT and sirtuin HDACs. Journal of Biological Chemistry, jbc-RA118.
The image is our submission for the JBC cover. It shows our favourite KAT (get it?) playing with GFP fused to an acetylation consensus sequence shared by Gcn5 KAT and sirtuins KDACS.
On the Left is our Cover submission - a KAT playing with our fusion protein used in the paper. Why didn’t it get picked for the cover? Your guess is as good as ours!
Take home message: A small peptide with a consensus sequence is sufficient to direct acetylation of non-histone targets.
A stringent analysis of polyphosphate dynamics in E. coli
Downey, M. (2019). A stringent analysis of polyphosphate dynamics in E. coli. Journal of bacteriology, JB-00070.
BioRxiv preprint version of E.Da Costa et al., 2018
Targeting MYC Overexpressing Leukemia with Cardiac Glycoside Proscillaridin Through Downregulation of Histone Acetyltransferases
From underlying chemistry to therapeutic potential: open questions in the new field of lysine polyphosphorylation
Bentley-DeSousa, Amanda, and Michael Downey. "From underlying chemistry to therapeutic potential: open questions in the new field of lysine polyphosphorylation." Current Genetics (2018): 1-8.
Take home message: Polyphosphorylation is really exciting, but there are important questions and caveats (but these are also exciting!).
Non-histone targets of KAT2A and KAT2B implicated in cancer biology
Bondy-Chorney, Emma, Alix Denoncourt, Yuka Sai, and Michael Downey. "Non-histone targets of KAT2A and KAT2B implicated in cancer biology." Biochemistry and Cell Biology ja (2018).
Take home message: GCN5 (KAT2A) and PCAF (KAT2B) make important contributions to cancer biology via non-histone protein acetylation.
A Screen for Candidate Targets of Lysine Polyphosphorylation Uncovers a Conserved Network Implicated in Ribosome Biogenesis
Amanda Bentley-DeSousa, Charlotte Holinier, Houman Moteshareie, Yi-Chieh Tseng, Sam Kajjo, Christine Nwosu, Giuseppe Federico Amodeo, Emma Bondy-Chorney, Yuka Sai, Adam Rudner, Ashkan Golshani, Norman E. Davey, Michael Downey. Cell Reports 2018 March 27, 2018.
The image to the right is our depiction of a polyphosphorylated protein that was selected as the cover.
New Finding: Polyphosphorylation might be a wide-spread modification in yeast. Moreover, human proteins can also be polyphosphorylated.
Nicotinamide Suppresses the DNA Damage Sensitivity of Saccharomyces cerevisiae Independently of Sirtuin Deacetylases
Rössl A, Bentley-DeSousa A, Tseng YC, Nwosu C, Downey M. Nicotinamide Suppresses the DNA Damage Sensitivity of Saccharomyces cerevisiae Independently of Sirtuin Deacetylases. Genetics. 2016 Aug 15. pii: genetics.116.193524.
Take home message: Beware of off target effects of your favourite inhibitors.
Building a KATalogue of acetyllysine targeting and function
Downey M, and Baetz K. 2015. Building a KATalogue of acetyllysine targeting and function.Briefings in Functional Genomics. Online ahead of print.
Hot take: Yeast is STILL the best system to study protein lysine acetylation.
Acetylome profiling reveals overlap in the regulation of diverse processes by sirtuins, Gcn5 and Esa1
Downey M, Johnson JR, Davey NE, Newton BW, Johnson TL, Galaang S, Seller CA, Krogan N, and Toczyski DP. (2014) Acetylome profiling reveals overlap in the regulation of diverse processes by sirtuins, Gcn5 and Esa1. Molecular and Cellular Proteomics, 14: 162-76.
Polymerase stalling during replication transcription and translation
Edenberg ER, Downey, M and Toczyski DP. (2014) Polymerase stalling during replication transcription and translation.Current Biology, 24: 445-452
Gcn5 and sirtuins regulate acetylation of the ribosomal protein transcription factor Ifh1
Downey M, Knight B, Vashisht AA, Seller CA, Wohlschlegel JA, Shore D, Toczyski DP. (2013) Gcn5 and sirtuins regulate acetylation of the ribosomal protein transcription factor Ifh1. Current Biology, 23:1638-1648.
Scaffolding reaches new heights at blocked replication forks
Downey M, Edenberg, ER, Toczyski, DP. (2010) Scaffolding reaches new heights at blocked replication forks. Molecular Cell, 39:162-164.
A genome wide screen identifies the evolutionarily conserved KEOPS complex as a telomere regulator
Downey M, Houlsworth R, Maringele L, Rollie A, Brehme M, Galicia S, Guillard S, Partington M, Zubko MK, Krogan NJ, Emili A, Greenblatt JF, Harrington L, Lydall D, and Durocher D. (2006) A genome wide screen identifies the evolutionarily conserved KEOPS complex as a telomere regulator. Cell, 124:1155-1168.
A genome-wide suppressor and enhancer analysis of cdc13-1 reveals varied cellular processes influencing telomere capping in Saccharomyces cerevisiae
Addinall SG,Downey M, Yu M, Zubko MK, Dewar J, Leake A, Hallinan J, Shaw O, James K, Wilkinson DJ, Wipat A, Durocher D, Lydall D. (2008) A genome-wide suppressor and enhancer analysis of cdc13-1 reveals varied cellular processes influencing telomere capping in Saccharomyces cerevisiae. Genetics, 180:2251-66.
Atomic structure of the KEOPS complex: an ancient protein kinase-containing molecular machine
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. (2008) Atomic structure of the KEOPS complex: an ancient protein kinase-containing molecular machine. Molecular Cell, 32:259-75.(*denotes co-first authorship)
Chromatin and DNA repair: the benefits of relaxation
Downey M and Durocher D. (2006) Chromatin and DNA repair: the benefits of relaxation. Nature Cell Biology, 8: 9-10.
gamma-H2AX as a checkpoint maintenance signal
Downey M and Durocher D. (2006) gamma-H2AX as a checkpoint maintenance signal. Cell Cycle,5:1376-1381.
A phosphatase complex that dephosphorylates gammaH2AX regulates DNA damage checkpoint recovery
Keogh MC*, Kim JA*, Downey M*, Fillingham J, Chowdhury D, Harrison JC, Onishi M, Datta N, Galicia S, Emili A, Lieberman J, Shen X, Buratowski S, Haber JE, Durocher D, Greenblatt JF, Krogan NJ. (2006) A phosphatase complex that dephosphorylates gammaH2AX regulates DNA damage checkpoint recovery. Nature, 439:497-501. (*denotes co-first authorship)
Proteomic analysis of SRm160-containing complexes reveals a conserved association with cohesin
McCracken S, Longman D, Marcon E, Moens P, Downey M, Nickerson JA, Jessberger R, Wilde A, Caceres JF, Emili A, Blencowe BJ. (2005) Proteomic analysis of SRm160-containing complexes reveals a conserved association with cohesin.J. Biol. Chem., 280:42227-36.
Distinct parts of minichromosome maintenance protein 2 associate with histone H3/H4 and RNA polymerase II holoenzyme
Holland, L., Downey, M., Song, X., Gauthier, L., Bell-Rogers, P. and Yankulov, K. (2002) Distinct parts of minichromosome maintenance protein 2 associate with histone H3/H4 and RNA polymerase II holoenzyme. Eur. J.Biochem., 269:5192-5202.