Over the last several years, accumulating evidence suggests that reversible acetylation may be a major regulatory mechanism for controlling protein function. Recent proteomic investigations have cataloged the existence of hundreds of acetylated proteins, implicating a potential regulatory role for nearly all facets of cellular biochemistry. Interestingly, metabolic enzymes constitute the largest portion of acetylated proteins. Only in a handful of examples has the functional significance of protein acetylation been revealed. Thus, there is tremendous need to determine the regulatory functions of protein acetylation, both at the level of physiological outcomes and at the level of molecular mechanism. This proposal directly investigates the central hypothesis that reversible acetylation is a major regulatory mechanism for controlling protein function. To accomplish these goals, we will investigate the biochemical and biological functions of sirtuins, NAD+dependent protein deacetylases, which are implicated in genome maintenance, metabolism, cell survival, and lifespan.
The specific aims are focused on demonstrating a direct regulatory role for sirtuins in several major metabolic processes, and elucidating how site-specific acetylation affects enzyme function. Employing mechanistic enzymology, quantitative mass spectrometry, novel high-throughput assays, metabolic pathway analysis, structural biology, enzyme regulation, cell culture models, and mouse genetics, these studies will provide the first comprehensive understanding of the functional significance of reversible protein acetylation. The results have the potential to uncover the prominence of a previously-unknown regulatory mechanism and to transform how we understand metabolic and aged-related diseases.

Public Health Relevance

New evidence suggests that a previously-unknown form of cellular and metabolic regulation exits. This proposal seeks to investigate the functional importance of this regulatory mechanism and the role played by a group of enzymes that are implicated in genome maintenance, metabolism, cell survival, and lifespan. The results have the potential to the transform how we understand metabolic and aged-related diseases, and to generate novel therapeutic opportunities.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
Project #
Application #
Study Section
Macromolecular Structure and Function E Study Section (MSFE)
Program Officer
Gerratana, Barbara
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Wisconsin Madison
Schools of Medicine
United States
Zip Code
Deota, Shaunak; Chattopadhyay, Tandrika; Ramachandran, Deepti et al. (2017) Identification of a Tissue-Restricted Isoform of SIRT1 Defines a Regulatory Domain that Encodes Specificity. Cell Rep 18:3069-3077
Sanders, Dean; Qian, Shuiming; Fieweger, Rachael et al. (2017) Histone Lysine-to-Methionine Mutations Reduce Histone Methylation and Cause Developmental Pleiotropy. Plant Physiol 173:2243-2252
Dhillon, Rashpal S; Denu, John M (2017) Using comparative biology to understand how aging affects mitochondrial metabolism. Mol Cell Endocrinol 455:54-61
Yu, Wei; Denu, Ryan A; Krautkramer, Kimberly A et al. (2016) Loss of SIRT3 Provides Growth Advantage for B Cell Malignancies. J Biol Chem 291:3268-79
Hullinger, Rikki; Li, Mi; Wang, Jingxin et al. (2016) Increased expression of AT-1/SLC33A1 causes an autistic-like phenotype in mice by affecting dendritic branching and spine formation. J Exp Med 213:1267-84
Fan, J; Baeza, J; Denu, J M (2016) Investigating Histone Acetylation Stoichiometry and Turnover Rate. Methods Enzymol 574:125-148
Gregg, Trillian; Poudel, Chetan; Schmidt, Brian A et al. (2016) Pancreatic ?-Cells From Mice Offset Age-Associated Mitochondrial Deficiency With Reduced KATP Channel Activity. Diabetes 65:2700-10
Baeza, Josue; Smallegan, Michael J; Denu, John M (2016) Mechanisms and Dynamics of Protein Acetylation in Mitochondria. Trends Biochem Sci 41:231-44
Dittenhafer-Reed, Kristin E; Richards, Alicia L; Fan, Jing et al. (2015) SIRT3 mediates multi-tissue coupling for metabolic fuel switching. Cell Metab 21:637-46
Kugel, Sita; Feldman, Jessica L; Klein, Mark A et al. (2015) Identification of and Molecular Basis for SIRT6 Loss-of-Function Point Mutations in Cancer. Cell Rep 13:479-488

Showing the most recent 10 out of 59 publications