A rare human centenarian variant of SIRT6 enhances genome stability and interaction with Lamin A
Year: 2022
Type: article
Study design: Observational Study
Abstract: 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.
Source: The EMBO Journal
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
Language: English
Subfield: Geriatrics and Gerontology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $6,100
Awards: G1169935680, G1242343652, G1375395185, G1642866419, G1761381014, Human tissue specific age-related gene expression changes, their genetic regulations and the link to human diseases, G2476700337, G2509259155, G2745100336, Combinatorial regulation of the enhancer codes in senescence, G2962823721, Role of Histone and Histone-like Mutations in the Oncogenesis of Human Cancers, G3373929068, Integrative Omics to enhance therapeutics development for healthy aging, G383750122, Combinatorial Actions of Genetic Variants and Gender Bias of Alzherimer's Disease, G4451993153, G5041377197, G6474419177, Systems Modeling of Alzheimers Disease in C. elegans, DNA Repair, Mutations and Cellular Aging, G9000045227, G9000047526, G9000097876, G9000117992, G9000141356, G9000197255, G9000235744, G9000334197, G9000340489, G9000344510, G9000355044, Comparative genomics of longevity and Alzheimer's disease, A Multi-scale Atlas of Senescence in Diverse Tissue Types, Regulation of epigenome stability by SIRT6 during Aging
OpenAlex ID: W4304140775