Balance between DNA repair, LINE1 suppression and lifespan in mice with SIRT6 Serine 10 phosphorylation site mutations

The relative importance of SIRT6 recruitment to DNA damage sites versus LINE1 transposons has not been investigated. SIRT6 Serine 10 phosphorylation promotes SIRT6 recruitment to the sites of DNA damage.

To explore the effect of SIRT6 Serine 10 phosphorylation on lifespan, we generated two SIRT6 mutant mouse strains: phospho-null S10A and phosphomimetic S10E. Unexpectedly, the S10E mutant mice demonstrated significantly enhanced DNA repair capacity associated with reduced lifespan in male mice compared to the wild-type and S10A mice. S10E mice also showed elevated LINE1 expression suggesting that SIRT6 S10E mutation enhances DNA repair capacity at the expense of reduced LINE1 silencing.