People

Dr. Zachara earned her B.Tech (Biotechnology) with First Class Honors and her Ph.D. from Macquarie University in Sydney, Australia. Her doctoral research, conducted under the mentorship of Dr. Nicolle Packer, Dr. Andrew Gooley, and Professor Keith L. Williams, focused on developing innovative technologies to map and quantify site-specific changes in protein glycosylation. She completed her postdoctoral training at Johns Hopkins University with Professor Gerald W. Hart, where she identified a critical role for O-GlcNAc in regulating the cellular stress response. Dr. Zachara’s laboratory investigates the molecular mechanisms by which O-GlcNAc prevents cytotoxicity, how cells regulate O-GlcNAc levels during stress, and how this stress-responsive glycosylation pathway can be harnessed to reduce tissue damage in models of injury.

Research Interests

O-GlcNAc is a post-translational modification found on thousands of intracellular proteins, including transcription factors, kinases, and cytoskeletal components. It plays a critical role in regulating diverse cellular processes such as protein folding and stability, localization, activity, post-translational modifications, and protein-protein interactions. Cells coordinate these molecular events across a wide array of proteins in response to environmental and physiological cues, thereby fine-tuning epigenetics, transcription, translation, signal transduction, cell cycle progression, and metabolism. The cellular stress response is no exception – various forms of injury trigger dynamic changes in the O-GlcNAc-subproteome that promote survival. Research in our laboratory broadly focuses on two key questions:
Which proteins are dynamically modified by O-GlcNAc in response to injury, and how does this modification alter their function to support cell survival?
How are the enzymes that add and remove O-GlcNAc regulated during cellular stress?
We address these questions using a combination of traditional biochemical and glycobiology techniques, high-throughput technologies, and genetic manipulation.

Select Publications

Narayanan B, Sinha P, Henry R, Reeves RA, Paolocci N, Kohr MJ, Zachara NE. Cardioprotective O-GlcNAc signaling is elevated in murine female hearts via enhanced O-GlcNAc transferase activity. J Biol Chem. 2023 Dec;299(12):105447. doi: 10.1016/j.jbc.2023.105447. Epub 2023 Nov 8. PMID: 37949223; PMCID: PMC10711226.
https://pubmed.ncbi.nlm.nih.gov/37949223/

Papanicolaou KN, Jung J, Ashok D, Zhang W, Modaressanavi A, Avila E, Foster DB, Zachara NE, O’Rourke B. Inhibiting O-GlcNAcylation impacts p38 and Erk1/2 signaling and perturbs cardiomyocyte hypertrophy. J Biol Chem. 2023 Mar;299(3):102907. doi: 10.1016/j.jbc.2023.102907. Epub 2023 Jan 13. PMID: 36642184; PMCID: PMC9988579.
https://pubmed.ncbi.nlm.nih.gov/36642184/

Martinez M, Renuse S, Kreimer S, O’Meally R, Natov P, Madugundu AK, Nirujogi RS, Tahir R, Cole R, Pandey A, Zachara NE. Quantitative Proteomics Reveals that the OGT Interactome Is Remodeled in Response to Oxidative Stress. Mol Cell Proteomics. 2021;20:100069. doi: 10.1016/j.mcpro.2021.100069. Epub 2021 Mar 12. PMID: 33716169; PMCID: PMC8079276.
https://pubmed.ncbi.nlm.nih.gov/33716169/

Umapathi P, Mesubi OO, Banerjee PS, Abrol N, Wang Q, Luczak ED, Wu Y, Granger JM, Wei AC, Reyes Gaido OE, Florea L, Talbot CC Jr, Hart GW, Zachara NE, Anderson ME. Excessive O-GlcNAcylation Causes Heart Failure and Sudden Death. Circulation. 2021 Apr 27;143(17):1687-1703. doi: 10.1161/CIRCULATIONAHA.120.051911. Epub 2021 Feb 17. PMID: 33593071; PMCID: PMC8085112.
https://pubmed.ncbi.nlm.nih.gov/33593071/

Mesubi OO, Rokita AG, Abrol N, Wu Y, Chen B, Wang Q, Granger JM, Tucker-Bartley A, Luczak ED, Murphy KR, Umapathi P, Banerjee PS, Boronina TN, Cole RN, Maier LS, Wehrens XH, Pomerantz JL, Song LS, Ahima RS, Hart GW, Zachara NE, Anderson ME. Oxidized CaMKII and O-GlcNAcylation cause increased atrial fibrillation in diabetic mice by distinct mechanisms. J Clin Invest. 2021 Jan 19;131(2):e95747. doi: 10.1172/JCI95747. PMID: 33151911; PMCID: PMC7810480.
https://pubmed.ncbi.nlm.nih.gov/33151911/

Taparra K, Wang H, Malek R, Lafargue A, Barbhuiya MA, Wang X, Simons BW, Ballew M, Nugent K, Groves J, Williams RD, Shiraishi T, Verdone J, Yildirir G, Henry R, Zhang B, Wong J, Wang KK, Nelkin BD, Pienta KJ, Felsher D, Zachara NE, Tran PT. O-GlcNAcylation is required for mutant KRAS-induced lung tumorigenesis. J Clin Invest. 2018 Nov 1;128(11):4924-4937. doi: 10.1172/JCI94844. Epub 2018 Sep 24. PMID: 30130254; PMCID: PMC6205381.
https://pubmed.ncbi.nlm.nih.gov/30130254/

Groves JA, Maduka AO, O’Meally RN, Cole RN, Zachara NE. Fatty acid synthase inhibits the O-GlcNAcase during oxidative stress. J Biol Chem. 2017 Apr 21;292(16):6493-6511. doi: 10.1074/jbc.M116.760785. Epub 2017 Feb 23. PMID: 28232487; PMCID: PMC5399103.
https://pubmed.ncbi.nlm.nih.gov/28232487/

Lee A, Miller D, Henry R, Paruchuri VD, O’Meally RN, Boronina T, Cole RN, Zachara NE. Combined Antibody/Lectin Enrichment Identifies Extensive Changes in the O-GlcNAc Sub-proteome upon Oxidative Stress. J Proteome Res. 2016 Dec 2;15(12):4318-4336. doi: 10.1021/acs.jproteome.6b00369. Epub 2016 Oct 14. PMID: 27669760; PMCID: PMC8132933.
https://pubmed.ncbi.nlm.nih.gov/27669760/

Zhu Y, Liu TW, Madden Z, Yuzwa SA, Murray K, Cecioni S, Zachara N, Vocadlo DJ. Post-translational O-GlcNAcylation is essential for nuclear pore integrity and maintenance of the pore selectivity filter. J Mol Cell Biol. 2016 Feb;8(1):2-16. doi: 10.1093/jmcb/mjv033. Epub 2015 Jun 1. PMID: 26031751; PMCID: PMC4710208.
https://pubmed.ncbi.nlm.nih.gov/26031751/

Zhong J, Martinez M, Sengupta S, Lee A, Wu X, Chaerkady R, Chatterjee A, O’Meally RN, Cole RN, Pandey A, Zachara NE. Quantitative phosphoproteomics reveals crosstalk between phosphorylation and O-GlcNAc in the DNA damage response pathway. Proteomics. 2015 Jan;15(2-3):591-607. doi: 10.1002/pmic.201400339. PMID: 25263469; PMCID: PMC4564869.
https://pubmed.ncbi.nlm.nih.gov/25263469/