SIRT6 in long-lived mammals has more sites for phosphate tags than in short-lived species
SIRT6 in long-lived mammals has more sites for phosphate tags than in short-lived species
Vera Gorbunova and Andrei Seluanov's group linked this feature to stronger interaction between SIRT6, a protein involved in DNA repair, and PARP1. PARP1 recognizes DNA damage and recruits repair proteins. In human cells, mimicking one phosphate tag helped the cells survive oxidative damage.
In a paper published on July 8, the researchers examined the flexible C-terminal tail of SIRT6. Phosphorylation is the addition of a phosphate group to a protein. It changes the protein's electrical charge and its interactions with other proteins. The authors compared SIRT6 sequences from more than 150 mammals with the species' maximum lifespans. Longer-lived species had more potential sites for phosphate tags on this tail.
One of these sites, T294, is present in humans but absent in mice. Using CRISPR, a method for making targeted changes to DNA, the researchers replaced T294 in human fibroblasts, which are connective tissue cells. The T294E variant mimics phosphorylation. After treatment with hydrogen peroxide, cells carrying this variant survived better. The T294A variant prevents phosphorylation at this position. SIRT6 carrying this substitution bound less strongly to PARP1.
The comparison across species links the number of potential phosphorylation sites to maximum lifespan. The authors identified these sites from protein sequences, but they measured the amount of phosphorylated SIRT6 only in cells from several species. After accounting simultaneously for body mass and relatedness among species, the association between T294 and longevity was not strong enough to support a firm conclusion. Further testing therefore requires mice carrying a targeted substitution in the Sirt6 gene, with health and lifespan measured in the same experiment.
In a February preprint from the same laboratory, the researchers introduced a permanent phosphorylation mimic at another SIRT6 site, S10E, in mice. DNA repair after irradiation was better in these mice. Median lifespan in males decreased by 10%. After irradiation, LINE1 expression was higher in blood cells from S10E mice. The authors also observed a trend toward higher LINE1 expression in the intestine and brain in individual groups. LINE1 elements are mobile, repetitive regions of the genome that generate new DNA copies. When LINE1 DNA accumulates in the cytoplasm, it activates an inflammatory response. The authors propose that weaker control of this process shortened the lifespan of male S10E mice.
A mouse experiment testing T294 should measure DNA repair, LINE1 suppression, inflammation, and lifespan from the outset. Together, these results would show whether enhanced DNA repair preserves protection against LINE1 and whether T294 changes lifespan.