期刊
EMBO JOURNAL
卷 41, 期 21, 页码 -出版社
WILEY
DOI: 10.15252/embj.2021110393
关键词
centenarians; lamin; longevity; SIRT6
资金
- US National Institute of Health [AG056278, AG027237, AG064706, AG064704, AG046320, AG047200, AG051449, AG076040, AG057433, AG061521, AG055501, AG057341, AG057706, AG057909, AG17242]
- Global Consortium for Reproductive Longevity and Equality at the Buck Institute [GCRLE-1320]
- Michael Antonov Foundation
- Simons Foundation
A variant of the enzyme SIRT6 (centSIRT6) may contribute to human longevity by improving genome maintenance through enhanced mADPr activity and an enhanced interaction with LMNA. This variant is a stronger suppressor of LINE1 retrotransposons, stimulates DNA double-strand break repair more effectively, and kills cancer cells more robustly compared to the wild-type SIRT6. Surprisingly, centSIRT6 exhibits weaker deacetylase activity but stronger mADPr activity.
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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