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A rare human centenarian variant of SIRT6 enhances genome stability and interaction with Lamin A.
Simon, Matthew; Yang, Jiping; Gigas, Jonathan; Earley, Eric J; Hillpot, Eric; Zhang, Lei; Zagorulya, Maria; Tombline, Greg; Gilbert, Michael; Yuen, Samantha L; Pope, Alexis; Van Meter, Michael; Emmrich, Stephan; Firsanov, Denis; Athreya, Advait; Biashad, Seyed Ali; Han, Jeehae; Ryu, Seungjin; Tare, Archana; Zhu, Yizhou; Hudgins, Adam; Atzmon, Gil; Barzilai, Nir; Wolfe, Aaron; Moody, Kelsey; Garcia, Benjamin A; Thomas, David D; Robbins, Paul D; Vijg, Jan; Seluanov, Andrei; Suh, Yousin; Gorbunova, Vera.
Afiliação
  • Simon M; Department of Biology, University of Rochester, Rochester, NY, USA.
  • Yang J; Department of Obstetrics and Gynecology, Columbia University, New York, NY, USA.
  • Gigas J; Department of Biology, University of Rochester, Rochester, NY, USA.
  • Earley EJ; Biostatistics and Epidemiology, RTI International, Durham, NC, USA.
  • Hillpot E; Department of Biology, University of Rochester, Rochester, NY, USA.
  • Zhang L; Department of Biochemistry, Molecular Biology and Biophysics and Institute on the Biology of Aging and Metabolism, University of Minnesota, Minneapolis, MN, USA.
  • Zagorulya M; Department of Biology, University of Rochester, Rochester, NY, USA.
  • Tombline G; Department of Biology, University of Rochester, Rochester, NY, USA.
  • Gilbert M; Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • Yuen SL; Department of Biochemistry, Molecular Biology and Biophysics and Institute on the Biology of Aging and Metabolism, University of Minnesota, Minneapolis, MN, USA.
  • Pope A; Department of Obstetrics and Gynecology, Columbia University, New York, NY, USA.
  • Van Meter M; Department of Biology, University of Rochester, Rochester, NY, USA.
  • Emmrich S; Department of Biology, University of Rochester, Rochester, NY, USA.
  • Firsanov D; Department of Biology, University of Rochester, Rochester, NY, USA.
  • Athreya A; Department of Biology, University of Rochester, Rochester, NY, USA.
  • Biashad SA; Department of Biology, University of Rochester, Rochester, NY, USA.
  • Han J; Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, USA.
  • Ryu S; Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, USA.
  • Tare A; Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, USA.
  • Zhu Y; Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, USA.
  • Hudgins A; Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, USA.
  • Atzmon G; Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, USA.
  • Barzilai N; Department of Biology, Faculty of Natural Sciences, University of Haifa, Haifa, Israel.
  • Wolfe A; Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, USA.
  • Moody K; Ichor Therapeutics, Lafayette, NY, USA.
  • Garcia BA; Ichor Therapeutics, Lafayette, NY, USA.
  • Thomas DD; Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • Robbins PD; Department of Biochemistry, Molecular Biology and Biophysics and Institute on the Biology of Aging and Metabolism, University of Minnesota, Minneapolis, MN, USA.
  • Vijg J; Department of Biochemistry, Molecular Biology and Biophysics and Institute on the Biology of Aging and Metabolism, University of Minnesota, Minneapolis, MN, USA.
  • Seluanov A; Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, USA.
  • Suh Y; Department of Biology, University of Rochester, Rochester, NY, USA.
  • Gorbunova V; Department of Obstetrics and Gynecology, Columbia University, New York, NY, USA.
EMBO J ; 41(21): e110393, 2022 11 02.
Article em En | MEDLINE | ID: mdl-36215696
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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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Sirtuínas / Lamina Tipo A Tipo de estudo: Prognostic_studies Limite: Aged80 / Humans Idioma: En Revista: EMBO J Ano de publicação: 2022 Tipo de documento: Article País de afiliação: Estados Unidos
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Sirtuínas / Lamina Tipo A Tipo de estudo: Prognostic_studies Limite: Aged80 / Humans Idioma: En Revista: EMBO J Ano de publicação: 2022 Tipo de documento: Article País de afiliação: Estados Unidos