TY - JOUR T1 - A rare human centenarian variant of SIRT6 enhances genome stability and interaction with Lamin A JF - bioRxiv DO - 10.1101/2021.12.13.472381 SP - 2021.12.13.472381 AU - Matthew Simon AU - Jiping Yang AU - Jonathan Gigas AU - Eric J. Earley AU - Tory M. Schaff AU - Lei Zhang AU - Maria Zagorulya AU - Greg Tombline AU - Michael Gilbert AU - Samantha L. Yuen AU - Alexis Pope AU - Michael Van Meter AU - Stephan Emmrich AU - Jeehae Han AU - Seungjin Ryu AU - Archana Tare AU - Yizhou Zhu AU - Adam Hudgins AU - Gil Atzmon AU - Nir Barzilai AU - Aaron Wolfe AU - Kelsey Moody AU - Benjamin A. Garcia AU - David D. Thomas AU - Paul D. Robbins AU - Jan Vijg AU - Andrei Seluanov AU - Yousin Suh AU - Vera Gorbunova Y1 - 2021/01/01 UR - http://biorxiv.org/content/early/2021/12/13/2021.12.13.472381.abstract N2 - 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. ER -