학술논문
A rare human centenarian variant of SIRT6 enhances genome stability and interaction with Lamin A.
Document Type
Article
Author
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
Source
Subject
*MISSENSE mutation
*CENTENARIANS
*DOUBLE-strand DNA breaks
*SIRTUINS
*MICROSATELLITE repeats
*GENOMES
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Language
ISSN
0261-4189
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. Synopsis: Two linked missense mutations in the C‐terminus of SIRT6 are enriched in human centenarians. The centenarian SIRT6 allele confers improved genome maintenance including DNA repair and LINE1 retrotransposon silencing.Two linked missense mutations in the C‐terminus of SIRT6 are enriched in human centenarians and in people older than 75.A centenarian allele of SIRT6 has reduced deacetylase/enhanced ribosylase activity compared to wild‐type SIRT6.The centenarian SIRT6 allele enhances genome maintenance, including more efficient DNA double strand break repair and LINE1 retrotransposon suppression.The centenarian SIRT6 associates more strongly with Lamin A. [ABSTRACT FROM AUTHOR]