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

Matthew Simon, Jiping Yang, Jonathan Gigas, Eric J. Earley, Tory M. Schaff, Lei Zhang, Maria Zagorulya, Greg Tombline, Michael Gilbert, Samantha L. Yuen, Alexis Pope, Michael Van Meter, View ORCID ProfileStephan Emmrich, 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, View ORCID ProfileVera Gorbunova
doi: https://doi.org/10.1101/2021.12.13.472381
Matthew Simon
1Department of Biology, University of Rochester; Rochester NY 14627, USA
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Jiping Yang
2Department of Obstetrics and Gynecology, Columbia University; New York, NY 10032, USA
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Jonathan Gigas
1Department of Biology, University of Rochester; Rochester NY 14627, USA
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Eric J. Earley
3Biostatistics and Epidemiology, RTI International, Durham, NC, USA
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Tory M. Schaff
4Department of Biochemistry, Molecular Biology and Biophysics and Institute on the Biology of Aging and Metabolism, University of Minnesota; Minneapolis, MN 55455
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Lei Zhang
4Department of Biochemistry, Molecular Biology and Biophysics and Institute on the Biology of Aging and Metabolism, University of Minnesota; Minneapolis, MN 55455
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Maria Zagorulya
1Department of Biology, University of Rochester; Rochester NY 14627, USA
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Greg Tombline
1Department of Biology, University of Rochester; Rochester NY 14627, USA
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Michael Gilbert
5Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania; Philadelphia, Pennsylvania 19104, USA
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Samantha L. Yuen
4Department of Biochemistry, Molecular Biology and Biophysics and Institute on the Biology of Aging and Metabolism, University of Minnesota; Minneapolis, MN 55455
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Alexis Pope
2Department of Obstetrics and Gynecology, Columbia University; New York, NY 10032, USA
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Michael Van Meter
1Department of Biology, University of Rochester; Rochester NY 14627, USA
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Stephan Emmrich
1Department of Biology, University of Rochester; Rochester NY 14627, USA
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  • ORCID record for Stephan Emmrich
Jeehae Han
6Department of Genetics, Albert Einstein College of Medicine; Bronx, NY, USA
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Seungjin Ryu
6Department of Genetics, Albert Einstein College of Medicine; Bronx, NY, USA
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Archana Tare
6Department of Genetics, Albert Einstein College of Medicine; Bronx, NY, USA
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Yizhou Zhu
6Department of Genetics, Albert Einstein College of Medicine; Bronx, NY, USA
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Adam Hudgins
6Department of Genetics, Albert Einstein College of Medicine; Bronx, NY, USA
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Gil Atzmon
6Department of Genetics, Albert Einstein College of Medicine; Bronx, NY, USA
7Department of Biology, Faculty of Natural Sciences, University of Haifa; Haifa, Israel 31905
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Nir Barzilai
6Department of Genetics, Albert Einstein College of Medicine; Bronx, NY, USA
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Aaron Wolfe
8Ichor Therapeutics; 2521 US-11, Lafayette, NY 13084, USA
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Kelsey Moody
8Ichor Therapeutics; 2521 US-11, Lafayette, NY 13084, USA
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Benjamin A. Garcia
5Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania; Philadelphia, Pennsylvania 19104, USA
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David D. Thomas
4Department of Biochemistry, Molecular Biology and Biophysics and Institute on the Biology of Aging and Metabolism, University of Minnesota; Minneapolis, MN 55455
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Paul D. Robbins
4Department of Biochemistry, Molecular Biology and Biophysics and Institute on the Biology of Aging and Metabolism, University of Minnesota; Minneapolis, MN 55455
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Jan Vijg
6Department of Genetics, Albert Einstein College of Medicine; Bronx, NY, USA
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Andrei Seluanov
2Department of Obstetrics and Gynecology, Columbia University; New York, NY 10032, USA
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  • For correspondence: andrei.seluanov@rochester.edu ys3214@cumc.columbia.edu vera.gorbunova@rochester.edu
Yousin Suh
3Biostatistics and Epidemiology, RTI International, Durham, NC, USA
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  • For correspondence: andrei.seluanov@rochester.edu ys3214@cumc.columbia.edu vera.gorbunova@rochester.edu
Vera Gorbunova
2Department of Obstetrics and Gynecology, Columbia University; New York, NY 10032, USA
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  • ORCID record for Vera Gorbunova
  • For correspondence: andrei.seluanov@rochester.edu ys3214@cumc.columbia.edu vera.gorbunova@rochester.edu
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SUMMARY

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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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted December 13, 2021.
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A rare human centenarian variant of SIRT6 enhances genome stability and interaction with Lamin A
Matthew Simon, Jiping Yang, Jonathan Gigas, Eric J. Earley, Tory M. Schaff, Lei Zhang, Maria Zagorulya, Greg Tombline, Michael Gilbert, Samantha L. Yuen, Alexis Pope, Michael Van Meter, Stephan Emmrich, 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
bioRxiv 2021.12.13.472381; doi: https://doi.org/10.1101/2021.12.13.472381
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A rare human centenarian variant of SIRT6 enhances genome stability and interaction with Lamin A
Matthew Simon, Jiping Yang, Jonathan Gigas, Eric J. Earley, Tory M. Schaff, Lei Zhang, Maria Zagorulya, Greg Tombline, Michael Gilbert, Samantha L. Yuen, Alexis Pope, Michael Van Meter, Stephan Emmrich, 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
bioRxiv 2021.12.13.472381; doi: https://doi.org/10.1101/2021.12.13.472381

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