With this award, the Chemistry of Life Processes Program in the Chemistry Division is funding Dr. Yana Cen from Virginia Commonwealth University to study the allosteric regulation of the human SIRT6 enzyme by breaks in damaged DNA. The role of human DNA in the transmission of hereditary information is supported by enzymes that support or suppress the transfer of information or repair DNA damaged by environmental factors. Sistuins are a family of such enzymes. SIRT6 is a member of the family that has weak in vitro activity and robust in vivo activity. Based on this information, scientists have formulated the hypothesis that the enzyme can be activated in response to DNA damages in cells. This project aims at elucidating the molecular mechanism underlying this activation using innovative small molecule probes and novel biochemical and cellular assays. The study seeks to elucidate how the regulation of SIRT6 activity takes place in cells and to suggest possible strategies for effective SIRT6 activation. The concurrent aim of this proposal is to provide a broadly accessible research experience for a large number of students across multiple academic levels. The comprehensive plan includes the mentoring of undergraduates, graduates and PharmD students as well as an outreach program offered to high school AP biology students. A PI-graduate student working group is to be established to develop and implement new guidelines for training in the interdisciplinary field of chemical biology.
SIRT6 is a chromatin-associated enzyme that plays a role in the epigenetic modification of DNA and has been implicated in the regulation of gene silencing, genome stability, DNA repair, and glucose homeostasis. The research objective of this project is to take a highly integrative chemical biology approach to interrogate the allosteric activation of SIRT6 by DNA strand breaks. The research seeks to identify the site where DNA binds to SIRT6 and to elucidate the activation mechanism triggered by this interaction. The project also involves a detailed spatio-temporal analysis of how SIRT6 is recruited and activated by DNA lesions using a combination of cellular and biophysical approaches. Additionally, the effect of DNA strand breaks on SIRT6 deacylation, a recently discovered activity of SIRT6, is assessed using wild type SIRT6 as well as a mutant SIRT6 with robust deacylase activity but significantly reduced deacetylase activity.
This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.
