A rare human centenarian variant of SIRT6 enhances genome stability and interaction with Lamin A

Matthew A. Simon; Jiping Yang; Jonathan Gigas; Eric J. Earley; Eric C. Hillpot; Lei Justan Zhang; Maria Zagorulya; Greg Tombline; Michael B. Gilbert; Samantha L. Yuen; Alexis Pope; Michael Van Meter; Stephan Emmrich; Denis Firsanov; Advait Athreya; Seyed Ali Biashad; Jeehae Han; Seungjin Ryu; Archana Tare; Yizhou Zhu; Adam D. Hudgins; Gil Atzmon; Nir Barzilai; Aaron J. Wolfe; Kelsey J. Moody; Benjamin A. Garcia; David Dale Thomas; Paul D. Robbins; Jan Vijg; Andrei Seluanov

doi:10.15252/embj.2021110393

Molecular BiologyThe EMBO JournalOct 10, 2022

Peer-reviewed journal article

A rare human centenarian variant of SIRT6 enhances genome stability and interaction with Lamin A

Matthew A. Simon iD, Jiping Yang iD, Jonathan Gigas iD, Eric J. Earley iD, Eric C. Hillpot, Lei Justan Zhang iD, Maria Zagorulya iD, Greg Tombline, Michael B. Gilbert iD, Samantha L. Yuen iD, Alexis Pope, Michael Van Meter, Stephan Emmrich iD, Denis Firsanov iD, Advait Athreya iD, Seyed Ali Biashad iD, Jeehae Han, Seungjin Ryu iD, Archana Tare, Yizhou Zhu iD, Adam D. Hudgins iD, Gil Atzmon iD, Nir Barzilai iD, Aaron J. Wolfe iD, Kelsey J. Moody iD, , Vera A. Gorbunova iD

Abstract

Sirtuin 6 (SIRT6) is a deacylase and mono-ADP ribosyl transferase (mADPr) enzyme involved in multiple cellular pathways implicated in the regulation of aging and metabolism. Targeted sequencing identified a SIRT6 allele containing two linked substitutions (N308K/A313S) as enriched in Ashkenazi Jewish (AJ) centenarians as compared to AJ control individuals. Characterization of this SIRT6 (centSIRT6) allele demonstrated it to be a stronger suppressor of LINE1 retrotransposons, confer enhanced stimulation of DNA double strand break repair, and more robust cancer cell killing compared to the wild type. Surprisingly, centSIRT6 displayed weaker deacetylase activity, but stronger mADPr activity, over a range of NAD+ concentrations and substrates. Additionally, centSIRT6 displayed a stronger interaction with Lamin A/C (LMNA), which correlated with enhanced ribosylation of LMNA. Our results suggest that enhanced SIRT6 function contributes to human longevity by improving genome maintenance via increased mADPr activity and enhanced interaction with LMNA.

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