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 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

doi:10.15252/embj.2021110393

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 journal › Article › peer-review

22 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 language	English (US)
Article number	e110393
Journal	EMBO Journal
Volume	41
Issue number	21
DOIs	https://doi.org/10.15252/embj.2021110393
State	Published - 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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.15252/embj.2021110393

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Simon, M., Yang, J., Gigas, J., Earley, E. J., Hillpot, E., Zhang, L., Zagorulya, M., Tombline, G., Gilbert, M., Yuen, S. L., Pope, A., Van Meter, M., Emmrich, S., Firsanov, D., Athreya, A., Biashad, S. A., Han, J., Ryu, S., Tare, A., ... Gorbunova, V. (2022). A rare human centenarian variant of SIRT6 enhances genome stability and interaction with Lamin A. EMBO Journal, 41(21), Article e110393. https://doi.org/10.15252/embj.2021110393

Simon, M, Yang, J, Gigas, J, Earley, EJ, Hillpot, E, Zhang, L, Zagorulya, M, Tombline, G, Gilbert, M, Yuen, SL, Pope, A, Van Meter, M, Emmrich, S, Firsanov, D, Athreya, A, Biashad, SA, Han, J, Ryu, S, Tare, A, Zhu, Y, Hudgins, A, Atzmon, G, Barzilai, N, Wolfe, A, Moody, K, Garcia, BA, Thomas, DD , Robbins, PD, Vijg, J, Seluanov, A, Suh, Y & Gorbunova, V 2022, 'A rare human centenarian variant of SIRT6 enhances genome stability and interaction with Lamin A', EMBO Journal, vol. 41, no. 21, e110393. https://doi.org/10.15252/embj.2021110393

@article{964234a8ea9b43a393a3188376851032,

title = "A rare human centenarian variant of SIRT6 enhances genome stability and interaction with Lamin A",

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.",

keywords = "centenarians, lamin, longevity, SIRT6",

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

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: {\textcopyright} 2022 The Authors. Published under the terms of the CC BY NC ND 4.0 license.",

year = "2022",

month = nov,

day = "2",

doi = "10.15252/embj.2021110393",

language = "English (US)",

volume = "41",

journal = "EMBO Journal",

issn = "0261-4189",

publisher = "EMBO Press",

number = "21",

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TY - JOUR

T1 - A rare human centenarian variant of SIRT6 enhances genome stability and interaction with Lamin A

AU - Simon, Matthew

AU - Yang, Jiping

AU - Gigas, Jonathan

AU - Earley, Eric J.

AU - Hillpot, Eric

AU - Zhang, Lei

AU - Zagorulya, Maria

AU - Tombline, Greg

AU - Gilbert, Michael

AU - Yuen, Samantha L.

AU - Pope, Alexis

AU - Van Meter, Michael

AU - Emmrich, Stephan

AU - Firsanov, Denis

AU - Athreya, Advait

AU - Biashad, Seyed Ali

AU - Han, Jeehae

AU - Ryu, Seungjin

AU - Tare, Archana

AU - Zhu, Yizhou

AU - Hudgins, Adam

AU - Atzmon, Gil

AU - Barzilai, Nir

AU - Wolfe, Aaron

AU - Moody, Kelsey

AU - Garcia, Benjamin A.

AU - Thomas, David D.

AU - Robbins, Paul D.

AU - Vijg, Jan

AU - Seluanov, Andrei

AU - Suh, Yousin

AU - Gorbunova, Vera

N1 - 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.

PY - 2022/11/2

Y1 - 2022/11/2

N2 - 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.

AB - 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.

KW - centenarians

KW - lamin

KW - longevity

KW - SIRT6

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DO - 10.15252/embj.2021110393

M3 - Article

C2 - 36215696

AN - SCOPUS:85139425278

SN - 0261-4189

VL - 41

JO - EMBO Journal

JF - EMBO Journal

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M1 - e110393

ER -

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

Abstract

Bibliographical note

Keywords

PubMed: MeSH publication types

UN SDGs

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