Investigating the role of phosphorylation in regulating the functions of mammalian sirtuin 6

摘要

Sirtuin 6 (SIRT6) is one of seven mammalian sirtuins, a family of evolutionarily conserved NAD+-dependent deacetylases/ mono-ADP ribosyltransferases with diverse sub-cellular localizations and functions. Sirtuins have been implicated in numerous cellular activities, including cell cycle regulation, apoptosis, stress response, DNA repair, gene expression, and possible modulation of lifespan. Most of the knowledge about sirtuins stems from studies on SIRT1- the founding mammalian family member, and its evolutionarily closest yeast homolog, Sir2. However, our understanding of the functions and interactions of other SIRTs remains very limited. Recent studies have indicated that SIRT6 may have roles in important processes such as DNA repair, NF-kB dependent gene expression, telomeric chromatin modulation, and aging. SIRT6 deficient mice develop metabolic deffects, display an aging-like phenotype, and die prematurely. In this study, we aim to further define the roles and means of regulation of SIRT6 from the perspective of its protein interactions and phosphorylation modifications. In approaching this goal we have integrated proteomics, molecular biology and microscopy approaches.