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.

中文翻译：

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SIRT6 的罕见人类百岁老人变体增强了基因组稳定性以及与核纤层蛋白 A 的相互作用


Sirtuin 6 (SIRT6) 是一种脱酰酶和单 ADP 核糖基转移酶 (mADPr)，参与与衰老和代谢调节有关的多种细胞途径。对 450 名德系犹太人 (AJ) 百岁老人和 550 名无长寿家族史的 AJ 个体进行 SIRT6 基因座靶向测序，发现与 AJ 对照个体相比，百岁老人中包含两个连锁取代 (N308K/A313S) 的 SIRT6 等位基因富集。该 SIRT6 等位基因 (centSIRT6) 的表征表明，与野生型 SIRT6 相比，它是 LINE1 逆转录转座子的更强抑制因子，增强了 DNA 双链断裂修复的刺激，并且更强有力地杀死癌细胞。令人惊讶的是，centSIRT6 在一定范围的 NAD ⁺浓度和底物上表现出较弱的脱乙酰酶活性，但具有较强的 mADPr 活性。此外，centSIRT6 显示出与核纤层蛋白 A/C (LMNA) 更强的相互作用，这与 LMNA 核糖基化的增强相关。我们的结果表明，增强的 SIRT6 功能通过增加 mADPr 活性和增强与 LMNA 的相互作用来改善基因组维护，从而有助于人类长寿。