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

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 ZhuAdam 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

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

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.

Original languageEnglish (US)
Article numbere110393
JournalEMBO Journal
Volume41
Issue number21
DOIs
StatePublished - Nov 2 2022

Bibliographical note

Funding Information:
We would like to extend a special thanks to Dr. Ivan Matic for providing the mADPr antibodies. We are thankful to Kevin Welle and Jennifer Hryhorenko of Mass Spectrometry Resource Lab for their help and advice. We would like to thank Meenakshisundaram Balasubramaniam and Robert Shmookler-Reis for their help in exploring SIRT6 structural changes. Funding was provided by the US National Institute of Health grants AG056278 (VG), AG027237 (VG), AG064706 (VG), AG064704 (VG), AG046320 (AS), AG047200 (VG and AS), AG051449 (VG and AS), AG056278 (YS), AG076040 (YS), AG057433 (YS), AG061521 (YS), AG055501 (YS), AG057341 (YS), AG057706 (YS), AG057909 (YS), and AG17242 (YS), a grant GCRLE-1320 (YS) from the Global Consortium for Reproductive Longevity and Equality at the Buck Institute, made possible by the Bia-Echo Foundation, a grant from the Michael Antonov Foundation, and a grant from the Simons Foundation (YS).

Funding Information:
We would like to extend a special thanks to Dr. Ivan Matic for providing the mADPr antibodies. We are thankful to Kevin Welle and Jennifer Hryhorenko of Mass Spectrometry Resource Lab for their help and advice. We would like to thank Meenakshisundaram Balasubramaniam and Robert Shmookler‐Reis for their help in exploring SIRT6 structural changes. Funding was provided by the US National Institute of Health grants AG056278 (VG), AG027237 (VG), AG064706 (VG), AG064704 (VG), AG046320 (AS), AG047200 (VG and AS), AG051449 (VG and AS), AG056278 (YS), AG076040 (YS), AG057433 (YS), AG061521 (YS), AG055501 (YS), AG057341 (YS), AG057706 (YS), AG057909 (YS), and AG17242 (YS), a grant GCRLE‐1320 (YS) from the Global Consortium for Reproductive Longevity and Equality at the Buck Institute, made possible by the Bia‐Echo Foundation, a grant from the Michael Antonov Foundation, and a grant from the Simons Foundation (YS).

Publisher Copyright:
© 2022 The Authors. Published under the terms of the CC BY NC ND 4.0 license.

Keywords

  • centenarians
  • lamin
  • longevity
  • SIRT6

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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