Long-lived mammals contain more phosphorylation sites in the SIRT6 C-terminus that enhance PARP1 interaction and resistance to oxidative stress.

Jonathan Gigas, Michael E Meadow, Jing Guo, Catherine Lan, Eric Hillpot, John C Martinez, Gregory Tombline, Philip Bellomio, Valeria Rivera-Almodóvar, Kevin A Welle, Kyle Swovick, Jennifer R Hryhorenko, Julia Ablaeva, Sina Ghaemmaghami, Andrei Seluanov, Vera Gorbunova

Department of Biology, University of Rochester, Rochester, NY, 14627, USA.Department of Biology, University of Rochester, Rochester, NY, 14627, USA. · pubmed

Paper

Abstract

Sirtuin 6 (SIRT6) is a protein deacetylase and ribosyltransferase that is a vital hub for maintaining epigenetic homeostasis, regulating the transcriptome, and repairing DNA double stranded breaks (DSBs). Comprehensive proteomic profiling of the SIRT6 posttranslational landscape, however, remains elusive. The SIRT6 C-terminal domain contains multiple phosphorylation sites. We find that the presence and the use of these sites are strongly correlated with maximum lifespan across mammals. Subsequent biochemical and in silico analyses revealed that SIRT6 hyperphosphorylation enhances its interaction with PARP1. Mutating the T294 phosphorylation site in human fibroblasts led to decreased survival after oxidative stress in the phospho-null T294A and improved oxidative stress resistance in the phospho-mimetic T294E. Together, these results suggest SIRT6 C-terminal phosphorylation increases stress resistance and interaction with PARP1 and that this phosphorylation is more abundant in long-lived mammalian species.

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Research summary

The study identifies a correlation between SIRT6 C-terminal phosphorylation, PARP1 interaction, and maximum lifespan across mammals, suggesting a mechanistic link between post-translational modifications and stress resistance. This work is relevant as it explores a fundamental molecular mechanism (SIRT6 regulation) associated with aging and longevity, though the findings are primarily correlative and incremental, lacking direct evidence of lifespan extension through intervention.

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