Investigator, Howard Hughes Medical Institute
Department of Chemistry and Chemical Biology, Cornell University
Department of Chemistry and Chemical Biology
Cells carry out numerous chemical reactions to achieve diverse biological functions. For example, phosphorylation of proteins is involved in many cell signaling processes, and histone acetylation and methylation provide epigenetic control. Of all the reactions that posttranslationally modify proteins, nicotinamide adenine dinucleotide (NAD)-consuming reactions control many biological processes, including transcription, aging, DNA repair, mitosis, and telomere maintenance, but they also display unique chemistry. Lin’s research focuses on NAD-consuming reactions in eukaryotic cells. His lab combines organic synthesis, biochemistry, and genetics to discover new reactions that consume NAD and new biological pathways that are regulated by known or new NAD-consuming reactions.
Lin’s lab is currently studying sirtuins, a family of enzymes with NAD-dependent deacylase activity that are important for aging, transcriptional regulation, and metabolism. His lab discovered that mammalian Sirt5 is a NAD-dependent desuccinylase and demalonylase. His lab also discovered the defatty-acylase activity of sirtuins, and it continues to identify novel activities of other mammalian sirtuins. These discoveries in turn enable his lab to design potent and selective inhibitors for specific sirtuins. Some of these inhibitors have demonstrated interesting and broad anticancer activities. Lin also studies poly(ADP ribose) polymerases, or PARPs, that catalyze protein poly(ADP-ribosyl)ation. PARPs are known to be required for DNA repair, transcriptional regulation, telomere extension, and mitosis. Lin’s lab uses organic synthesis to make various NAD analogues that, combined with biochemistry and RNA interference, allow the tagging and identification of substrate proteins of PARPs, which allow the discovery of biological pathways that are regulated by PARPs.
Jing, H. et al. A SIRT2-selective inhibitor promotes c-Myc oncoprotein degradation and exhibits broad anticancer activity. Cancer Cell 29, 297–310 (2016).
Jiang, H. et al. Sirt6 regulates TNF-α secretion through hydrolysis of long-chain fatty acyl lysine. Nature 496, 110–113 (2013).
Du, J. et al. Sirt5 is a NAD-dependent protein lysine demalonylase and desuccinylase. Science 334, 806–809 (2011).