A Rare Human Centenarian Variant of SIRT6 Enhances Genome Stability and Interaction with Lamin A

Overview

Journal EMBO J

Specialties Biotechnology
Molecular Biology

Date 2022 Oct 10

PMID 36215696

Authors

Matthew Simon

Jiping Yang

Jonathan Gigas

Eric J Earley

Eric Hillpot

Lei Zhang

Maria Zagorulya

Greg Tombline

Michael 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 Hudgins

Gil Atzmon

Nir Barzilai

Aaron Wolfe

Kelsey Moody

Benjamin A Garcia

David D Thomas

Paul D Robbins

Jan Vijg

Andrei Seluanov

Yousin Suh

Vera Gorbunova

Affiliations

Soon will be listed here.

Abstract

Sirtuin 6 (SIRT6) is a deacylase and mono-ADP ribosyl transferase (mADPr) enzyme involved in multiple cellular pathways implicated in aging and metabolism regulation. Targeted sequencing of SIRT6 locus in a population of 450 Ashkenazi Jewish (AJ) centenarians and 550 AJ individuals without a family history of exceptional longevity identified enrichment of a SIRT6 allele containing two linked substitutions (N308K/A313S) in centenarians compared with AJ control individuals. Characterization of this SIRT6 allele (centSIRT6) demonstrated it to be a stronger suppressor of LINE1 retrotransposons, confer enhanced stimulation of DNA double-strand break repair, and more robustly kill cancer cells compared with wild-type SIRT6. 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 was 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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