2. Academic Validation
  3. SIRT6 is a DNA double-strand break sensor

SIRT6 is a DNA double-strand break sensor

  • Elife. 2020 Jan 29;9:e51636. doi: 10.7554/eLife.51636.
Lior Onn 1 2,  Miguel Portillo 1 2,  Stefan Ilic 3,  Gal Cleitman 1 2,  Daniel Stein 1 2,  Shai Kaluski 1 2,  Ido Shirat 1 2,  Zeev Slobodnik 1 2,  Monica Einav 1 2,  Fabian Erdel 4 5,  Barak Akabayov 3,  Debra Toiber 1 2
Affiliations

Affiliations

  • 1 Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel.
  • 2 The Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
  • 3 Department of Chemistry, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
  • 4 Division of Chromatin Networks, German Cancer Research Center (DKFZ), BioQuant, Heidelberg, Germany.
  • 5 Centre de Biologie Intégrative, CNRS UPS, Toulouse, France.
PMID: 31995034 DOI: 10.7554/eLife.51636
Abstract

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.

Keywords

DNA damage; DNA repair; DSB; SIRT6; cell biology; human; sensor.

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