Education
- ACS accredited B.A., Chemistry with biochemistry emphasis Magna Cum Laude, Franklin and Marshall College, Lancaster, PA
- Ph.D., Biochemistry, University of Wisconsin – Madison, Madison, WI
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 homebrewing 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
- Fan J., Krautkramer K.A., Feldman J.L., Denu J.M. (2015) Metabolic regulation of histone post-translational modifications. ACS Chemical Biology. 10(1):95-108
- Cooley, R.B., Feldman, J.L., Driggers, C.M., Bundy, T., Stokes, A.L., Karplus P.A., Mehl, R.A. (2014) Structural basis of improved second generation 3-nitro-tyrosine tRNA synthetases. ACS Biochemistry. 53 (12), 1916–1924
- Feldman, J.L., Baeza, J., Denu, J.M. (2013) Activation of the protein deacetylase SIRT6 by long-chain fatty acids and widespread deacylation by the mammalian sirtuins. J. Biol. Chem. 288(43), 31350-31356 [Featured as a JBC Paper of the Week.]
- Franco, M.C., Ye, Y., Refakis, C.A., Feldman, J.L, Stokes, A.L., Basso, M., Fernández de Mera, R.M.M, Sparrow, N.A., Calingasan, N.Y., Kiaei, M., Rhoades, T.W., Ma, T., Grumet, M., Barnes, S., Beal, M.F., Beckman, J.S., Mehl, R., Estévez, A. (2013) Nitration of Hsp90 induces cell death. Proc Natl Acad Sci USA 110(12), E1102-1111
- Dominy J.E. Jr., Lee Y., Jedrychowski M.P., Chim H, Jurczak, M.J., Camporez J.P., Ruan H.B., Feldman J., Pierce K., Mostoslavsky R., Denu J.M., Clish C.B., Yang X., Shulman G.I., Gygi S.P., Puigserver P. (2012) The deacetylase SIRT6 activates the acetyltransferase GCN5 and suppresses hepatic gluconeogenesis. Mol. Cell 48, 1-14
- Feldman J.L.*, Dittenhafer-Reed K.E.*, Denu J.M. (2012) Sirtuin catalysis and regulation J. Biol. Chem. 276 (51), 42419-42427
- Pan, P. W.*, Feldman, J.L.*, Devries, M. K., Dong, A., Edwards, A. M., Denu, J. M. (2011) Structure and biochemical functions of SIRT6. J. Biol. Chem. 286(16), 14575-14587
- Dittenhafer-Reed, K. E.*, Feldman, J. L.*, Denu, J. M. (2011) Catalysis and mechanistic insights into sirtuin activation. ChemBioChem 12 (2), 281-289