Education
ACS accredited BA, Chemistry with biochemistry emphasis Magna Cum Laude, Franklin and Marshall College, Lancaster, PA
PhD, Biochemistry, University of Wisconsin-Madison
Research Description
SIRT6 is a member of the Sir2 family of NAD+-dependent protein deacylases. Mice deficient in SIRT6 have metabolic defects and genomic instability, leading to shortened life span. Despite in vivo evidence indicating that SIRT6 is an efficient histone deacetylase, SIRT6 displays very weak deacetylase activity in vitro. My research focuses on investigating the molecular mechanisms and regulation of SIRT6. Early work suggested that the inefficient activity is due to a less active conformation of the enzyme. Recently, we demonstrated that the catalytic activity of SIRT6 is directly activated by biologically relevant long-chain free fatty acids. These results further highlight the connection between metabolism, SIRT6, and epigenetic modulation. These observations suggest that the development of small-molecule activators of SIRT6 holds therapeutic potential to treat cancer, inflammation, and metabolic diseases. Utilizing biochemical, biophysical, structural, and cellular approaches, I hope to provide further insight into the important biological role of SIRT6 in metabolism and genomic stability. Outside of the lab, I enjoy playing basketball and softball, biking, going to Badger sporting events, and perfecting my home-brewing skills.
The crystal structure of SIRT6 oddly resembles a very happy whale.
Honors
FASEB Research Conference Travel Award, 2013
American Heart Association Predoctoral Fellow, 2011-2013
Phi Beta Kappa National Honor Society, 2009
Merck Index Award in Chemistry, 2009
Isaac E. Roberts Award in Biology, 2008
Selected Publications
*Denotes co-first author
Metabolic regulation of histone post-translational modifications. Fan J, Krautkramer KA, Feldman JL, Denu JM. ACS Chemical Biology 2015.
Structural basis of improved second generation 3-nitro-tyrosine tRNA synthetases. Cooley RB, Feldman JL, Driggers CM, Bundy T, Stokes AL, Karplus PA, Mehl RA. ACS Biochemistry 2014.
Activation of the protein deacetylase SIRT6 by long-chain fatty acids and widespread deacylation by the mammalian sirtuins. Feldman JL, Baeza J, Denu JM. J. Biol. Chem. 2013 [Featured as a JBC Paper of the Week.]
Nitration of Hsp90 induces cell death. Franco MC, Ye Y, Refakis CA, Feldman JL, Stokes AL, Basso M, Fernández de Mera RMM, Sparrow NA, Calingasan NY, Kiaei M, Rhoades TW, Ma T, Grumet M, Barnes S, Beal MF, Beckman JS, Mehl R, Estévez A. Proc Natl Acad Sci USA 2013.
The deacetylase SIRT6 activates the acetyltransferase GCN5 and suppresses hepatic gluconeogenesis. Dominy JE Jr., Lee Y, Jedrychowski MP, Chim H, Jurczak MJ, Camporez JP, Ruan HB, Feldman JL, Pierce K, Mostoslavsky R, Denu JM, Clish CB, Yang X, Shulman GI, Gygi SP, Puigserver P. Mol. Cell 2012.
Sirtuin catalysis and regulation. Feldman JL*, Dittenhafer-Reed KE*, Denu JM. J. Biol. Chem. 2012.
Structure and biochemical functions of SIRT6. Pan PW*, Feldman JL*, Devries MK, Dong A, Edwards AM, Denu JM. J. Biol. Chem. 2011.
Catalysis and mechanistic insights into sirtuin activation. Dittenhafer-Reed KE*, Feldman JL*, Denu JM. ChemBioChem 2011.