Chromatin and beyond: the multitasking roles for SIRT6

Abstract

In recent years there has been a large expansion in our understanding of SIRT6 biology, including its structure, regulation, biochemical activity and biological roles. SIRT6 functions as an ADP-ribosylase and NAD+-dependent deacylase of both acetyl groups and long-chain fatty acyl groups. Through these functions SIRT6 impacts cellular homeostasis by regulating DNA repair, telomere maintenance and glucose and lipid metabolism, thus affecting diseases such diabetes, obesity, heart disease, and cancer. Such roles may contribute to overall longevity and health of the organism. Until recently, much of the known functions of SIRT6 were restricted to the chromatin. In this article, we seek to describe and expand this knowledge with recent advances in understanding the mechanisms of SIRT6 action and their implications for human biology and disease.

Sirtuin-6 Preserves R-spondin-1 Expression and increases Resistance of intestinal Epithelium to injury in Mice

“…Emerging studies have shown that Sirt6 is a key regulator of genome stability, glucose homeostasis, metabolism and inflammation (9). It governs diverse cellular functions, such as transcription, telomere integrity and DNA repair (9).…”

“…It governs diverse cellular functions, such as transcription, telomere integrity and DNA repair (9). Mouse pups with whole-body Sirt6 with lipopolysaccharide resulted in downregulation of Rspo1 mRNA ( Supplementary Figure 3) and protein expression in colons ( Figure 7C).…”

“…controlling a number of metabolic and survival processes in cells (9). Recently, Kanfi et al reported that mice overexpressing Sirt6 have increased longevity (10).…”

“…Sirt6 knockout mice were found to die within one month after birth due to numerous abnormalities, including profound lymphopenia, loss of subcutaneous fat, lordokyphosis and severe metabolic defects (11). Evidence suggests that Sirt6 has both proinflammatory and antiinflammatory roles, depending on the context and cell type involved (9). Currently, the exact role of Sirt6 in intestinal epithelial cells remains unknown, and how it is affected during intestinal inflammation has not been explored.…”

Mechanisms of development of multimorbidity in the elderly

“…The natural product resveratrol activates SIRT1 and has led to the development of more potent SIRT1 activating compounds, which are now in development for the treatment of age-related diseases [128]. SIRT6 is an ADP-ribosylase as well as a protein deacetylase and plays a key role in regulating DNA repair, telomere maintenance and metabolic homeostasis and, like SIRT1, is linked to extension of lifespan [129]. Reduced SIRT6 has been implicated in COPD, atherosclerosis, obesity and type 2 diabetes [125,129].…”