Phosphorylation of the human SIRT6 protein on threonine 294 residue.

As a result of better healthcare and advanced medicine, in the last few decades there was an increase in average and maximal life expectancy. Elevated lifespan, along with a worldwide increase in elderly population, make aging-related diseases more prominent – cancer, metabolic disorders and neurodegenerative diseases, in addition to multiple cellular defects, such as cell senescence and DNA damage.

SIRT6 is a NAD⁺-dependent histone deacetylase that is strongly linked to animal maturation and aging. It plays a key role regulating major cellular and systemic pathways of gene expression, metabolism, DNA repair, etc. While knockout of SIRT6 in mice causes metabolic disorders and premature aging phenotypes, mice overexpressing SIRT6 live longer in a better health. In primates SIRT6 deficiency leads to severe embryonic developmental defects and prenatal death.

SIRT6 is highly conserved, nevertheless, the C-terminal region of the human SIRT6 differ from that of other mammals. We have found in this region a threonine residue (T294) that goes through phosphorylation under normal conditions in multiple tissues, in cancer and normal cells. Though the phosphorylation does not alter intrinsic activity of SIRT6, our results suggest a possible role of it in SIRT6-dependent regulation of cell differentiation and nutrient stress response.

Finding the mechanism of SIRT6 phosphorylation will provide us with a better understanding of SIRT6`s role in regulating cellular processes. Moreover, our results may suggest a new mechanism in the basis of SIRT6-mediated longevity in humans and get us a better approach to the development of drugs for aging-related diseases.