The Role of SIRT6 on Nuclear Organization

Aging is characterized by a progressive loss of physiological integrity, leading to impaired function and increased vulnerability to death. Some of the aging hallmarks are genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication (C. Lopez-otin, cell, 2013).

Histones are most known for their structural role but they also play an important role in regulation of gene expression. Modifications on histones, like methylation, acetylation and more can affect the accessibility of different factors to the DNA. This kind of regulation ensure that each cell type express different set of proteins corresponds with its function even though all the cells containing the same genetic material.

SIRT6 is an NAD+-dependent enzymes holding three enzymatic activities, deacetylation, deacylation and mono-ADP-ribosylation. The most studied substrates of SIRT6 are acetylated histones like H3K56Ac, H3K9Ac and H3K18Ac. SIRT6 transgenic mice exhibit significant extension of lifespan and better metabolic profile. To this time, it has been shown that SIRT6 can regulate a variety of biological processes, including DNA repair, glucose and lipid metabolism, and oxidative stress.

As many of the aging hallmarks are taking place in the nucleus and as the specific activity contributing to lifespan extension by SIRT6 is yet to be determined, we decided to focus on the effect of SIRT6 on the nuclear organization.