SIRT6 is a DNA Double-Strand Break Sensor
SIRT6 is a DNA Double-Strand Break Sensor
Abstract DNA double strand breaks are the most deleterious type of DNA damage. In this work, we show that SIRT6 directly recognizes DNA damage through a tunnel-like structure, with high affinity for double strand breaks. It relocates to sites of damage independently of signalling and known sensors and activates downstream signalling cascades for double strand break repair by triggering ATM recruitment, H2AX phosphorylation and the recruitment of proteins of the Homologous Recombination and Non-Homologous End Joining pathways. Our findings indicate that SIRT6 plays a previously uncharacterized role as DNA damage sensor, which is critical for initiating the DNA damage response (DDR). Moreover, other Sirtuins share some DSB binding capacity and DDR activation. SIRT6 activates the DDR, before the repair pathway is chosen, and prevents genomic instability. Our findings place SIRT6 at the top of the DDR and pave the road to dissect the contributions of distinct double strand break sensors in downstream signalling.
Slobodnik Zeev、Portillo Miguel、Einav Monica、Akabayov Barak、Toiber Debra、Shirat Ido、Cleitman Gal、Kaluski Shai、Erdel Fabian、Ilic Stefan、Onn Lior、Stein Daniel
Department of Life Sciences, Ben-Gurion University of the Negev||The Zlotowski Center for Neuroscience, Ben-Gurion University of the NegevDepartment of Life Sciences, Ben-Gurion University of the Negev||The Zlotowski Center for Neuroscience, Ben-Gurion University of the NegevDepartment of Life Sciences, Ben-Gurion University of the Negev||The Zlotowski Center for Neuroscience, Ben-Gurion University of the NegevDepartment of Chemistry, Ben-Gurion University of the NegevDepartment of Life Sciences, Ben-Gurion University of the Negev||The Zlotowski Center for Neuroscience, Ben-Gurion University of the NegevDepartment of Life Sciences, Ben-Gurion University of the Negev||The Zlotowski Center for Neuroscience, Ben-Gurion University of the NegevDepartment of Life Sciences, Ben-Gurion University of the Negev||The Zlotowski Center for Neuroscience, Ben-Gurion University of the NegevDepartment of Life Sciences, Ben-Gurion University of the Negev||The Zlotowski Center for Neuroscience, Ben-Gurion University of the NegevDivision of Chromatin Networks, German Cancer Research Center (DKFZ) and BioQuantDepartment of Chemistry, Ben-Gurion University of the NegevDepartment of Life Sciences, Ben-Gurion University of the Negev||The Zlotowski Center for Neuroscience, Ben-Gurion University of the NegevDepartment of Life Sciences, Ben-Gurion University of the Negev||The Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev
基础医学分子生物学生物化学
Slobodnik Zeev,Portillo Miguel,Einav Monica,Akabayov Barak,Toiber Debra,Shirat Ido,Cleitman Gal,Kaluski Shai,Erdel Fabian,Ilic Stefan,Onn Lior,Stein Daniel.SIRT6 is a DNA Double-Strand Break Sensor[EB/OL].(2025-03-28)[2025-08-02].https://www.biorxiv.org/content/10.1101/765172.点此复制
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