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<p>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.</p> Graphical Abstract <p></p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月8日

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  • 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

摘要

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.

Graphical Abstract