SIRT6 is a DNA double-strand break sensor

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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. SIRT6 relocates to sites of damage independently of signalling and known sensors. It activates downstream signalling for double strand break repair by triggering ATM recruitment, H2AX phosphorylation and the recruitment of proteins of 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 double strand break sensors in downstream signalling.

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All the data generated or analyzed during this study are included in the manuscript and supporting files.

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Lior Onn

Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel

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The authors declare that no competing interests exist.
Miguel Portillo

Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel

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The authors declare that no competing interests exist.
Stefan Ilic

Department of Chemistry, Ben-Gurion University of the Negev, Beer Sheva, Israel

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The authors declare that no competing interests exist.
Gal Cleitman

Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel

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The authors declare that no competing interests exist.
Daniel Stein

Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel

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Shai Kaluski

Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel

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Ido Shirat

Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel

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The authors declare that no competing interests exist.
Zeev Slobodnik

Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel

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Monica Einav

Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel

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Fabian Erdel

BioQuant, Heidelberg University, Heidelberg, Germany

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"This ORCID iD identifies the author of this article:" 0000-0003-2888-7777
Barak Akabayov

Department of Chemistry, Ben-Gurion University of the Negev, Beer Sheva, Israel

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The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-3882-2742
Debra Toiber

Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel

For correspondence
toiber@bgu.ac.il

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The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-1465-0130

Funding

Israel Science Foundation (188/17)

Debra Toiber

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

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This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.