# Sirt6 NAD+-Dependent Protein Deacetylase Inhibition by Cysteine S-nitrosation

> **NIH NIH F31** · MEDICAL COLLEGE OF WISCONSIN · 2020 · $20,124

## Abstract

PROJECT SUMMARY
Type-II diabetes is characterized by the inability of pancreatic beta cells to produce enough insulin to maintain
normal levels of blood glucose. In the development of diabetes, prolonged exposure of pancreatic beta cells to
macrophage-derived inflammatory cytokines can initiate nitric oxide (NO)-dependent beta cell dysfunction and
apoptosis. The sirtuin family (Sirt1-7) of NAD+-dependent protein deacylases are generally considered pro-
survival proteins, as decreased sirtuin activity is implicated in the development of several aging-related
diseases including type-II diabetes. The nuclear sirtuin Sirt6 is thought to be particularly important in
maintaining metabolic health and protecting against pancreatic beta cell dysfunction. The overall goal of this
proposal is to elucidate the response of Sirt6 to inflammatory conditions in beta cells. The sensitivity of Sirt6 to
posttranslational modification by NO and the impact of Sirt6 modification on beta cell DNA damage repair in
response to inflammatory cytokines will be tested in two Specific Aims. In Aim 1, we will test the hypothesis
that Sirt6 is S-nitrosated during beta cell inflammation. S-nitrosation is a NO-derived post-translational
modification of protein cysteine residues. We and others recently demonstrated that Sirt1 deacetylase activity
is reversibly inhibited by S-nitrosation of the Sirt1 Zn2+-tetrathiolate cysteine residues. The Zn2+-tetrathiolate is
conserved among all sirtuin isoforms and Sirt6, like Sirt1, is localized to the nucleus. Therefore, Sirt6 may be
inhibited by the same NO-dependent pathway as Sirt1. Indeed, our unpublished preliminary data shows that
Sirt6 is readily transnitrosated by NO and S-nitrosoglutathione in vitro, and S-nitrosation of Sirt6 correlates with
a decrease in Sirt6 deacetylase activity. In Aim 2, we will test the hypothesis that Sirt6 S-nitrosation inhibits
DNA damage repair in beta cells. Recent evidence points to a central role for DNA damage in the beta cells
that undergo apoptosis in response to cytokine treatment. Among the sirtuins, Sirt6 is uniquely implicated in
promoting DNA damage repair. Therefore, we will examine the impact of Sirt6 S-nitrosation in DNA damage
repair and beta cell survival. We will use biochemical, biophysical, chemical biological, cell biological, and
molecular biological tools and assays to evaluate the regulation of Sirt6 deacetylase activity in beta cells by S-
nitrosation and the impact on DNA damage repair processes in beta cells. We anticipate the mechanistic
insights gained from this work will improve understanding of type-II diabetes pathogenesis, with the long-term
goal of developing novel strategies for prevention or treatment of type-II diabetes.

## Key facts

- **NIH application ID:** 9944558
- **Project number:** 5F31DK117588-03
- **Recipient organization:** MEDICAL COLLEGE OF WISCONSIN
- **Principal Investigator:** Kelsey Shea Kalous
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $20,124
- **Award type:** 5
- **Project period:** 2018-06-18 → 2020-07-17

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9944558

## Citation

> US National Institutes of Health, RePORTER application 9944558, Sirt6 NAD+-Dependent Protein Deacetylase Inhibition by Cysteine S-nitrosation (5F31DK117588-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9944558. Licensed CC0.

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