The Sirtuins and SMCs: Regulators of Heterochromatin in Time and Space

With average length of human healthspan not matching the average length of lifespan, aging is perhaps the biggest obstacle facing modern society due to the economic and social burdens of dealing with chronic disease. Thus, it has become essential to discover mechanistic causes behind the aging process itself to devise strategies and eliminate this gap. In this regard, a large body of research has been conducted on the sirtuin family of NAD+-dependent protein deacetylases conserved from bacteria to humans. These fascinating enzymes link a cell’s metabolic state to protein acetylation status and epigenetic silencing of heterochromatin. General activation of sirtuins increases lifespan across a range of model organism from yeast to mice through increased stabilization of heterochromatic loci. Furthermore, dietary supplementation of precursors to the sirtuin activator, NAD+, increases healthspan in mice, suggesting a route for therapeutic interventions in humans. However, the seven human sirtuins play a wide array of roles and, in some cases, counter-act the effects of one another, warranting more investigation into their regulatory functions.
An equally conserved family of proteins known as the structural maintenance of chromosomes (SMCs) have been studied for roles in segregation of mitotic chromosomes. Yet, throughout the years of sirtuin driven heterochromatin research, the SMCs have time and time again displayed a number of roles in helping the nuclear sirtuins establish and maintain heterochromatic loci. While the SMCs generally work independently, there is extensive interplay between family members in driving chromosomal structural changes, especially within the nucleolus of a cell. More importantly, several SMC mutations cause a wide range of diseases in patients due to defects in heterochromatin as opposed to sister chromatid segregation. This thesis attempts to explore the mechanistic roles of both families within the context of heterochromatin.