Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel; The Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer-Sheva, Israel
Miguel Portillo
Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel; The Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer-Sheva, Israel
Stefan Ilic
Department of Chemistry, Ben-Gurion University of the Negev, Beer-Sheva, Israel
Gal Cleitman
Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel; The Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer-Sheva, Israel
Daniel Stein
Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel; The Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer-Sheva, Israel
Shai Kaluski
Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel; The Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer-Sheva, Israel
Ido Shirat
Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel; The Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer-Sheva, Israel
Zeev Slobodnik
Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel; The Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer-Sheva, Israel
Monica Einav
Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel; The Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer-Sheva, Israel
Division of Chromatin Networks, German Cancer Research Center (DKFZ), BioQuant, Heidelberg, Germany; Centre de Biologie Intégrative, CNRS UPS, Toulouse, France
Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel; The Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer-Sheva, Israel
DNA double-strand breaks (DSB) are the most deleterious type of DNA damage. In this work, we show that SIRT6 directly recognizes DNA damage through a tunnel-like structure that has high affinity for DSB. SIRT6 relocates to sites of damage independently of signaling and known sensors. It activates downstream signaling for DSB 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 a DNA damage sensor, a critical factor in 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 as a sensor of DSB, and pave the road to dissecting the contributions of distinct DSB sensors in downstream signaling.
