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Priority Research Paper|Volume 12, Issue 12|pp 11165—11184

SIRT6 mono-ADP ribosylates KDM2A to locally increase H3K36me2 at DNA damage sites to inhibit transcription and promote repair

Sarallah Rezazadeh1, David Yang1, Seyed Ali Biashad1, Denis Firsanov1, Masaki Takasugi1, Michael Gilbert1, Gregory Tombline1, Natarajan V. Bhanu2, Benjamin A. Garcia2, Andrei Seluanov1, Vera Gorbunova1
  • 1Department of Biology, University of Rochester, Rochester, NY 14627, USA
  • 2Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Received: May 9, 2020Accepted: June 9, 2020Published: June 25, 2020
https://doi.org/10.18632/aging.103567

Copyright © 2020 Rezazadeh et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

When transcribed DNA is damaged, the transcription and DNA repair machineries must interact to ensure successful DNA repair. The mechanisms of this interaction in the context of chromatin are still being elucidated. Here we show that the SIRT6 protein enhances non-homologous end joining (NHEJ) DNA repair by transiently repressing transcription. Specifically, SIRT6 mono-ADP ribosylates the lysine demethylase JHDM1A/KDM2A leading to rapid displacement of KDM2A from chromatin, resulting in increased H3K36me2 levels. Furthermore, we found that through HP1α binding, H3K36me2 promotes subsequent H3K9 tri-methylation. This results in transient suppression of transcription initiation by RNA polymerase II and recruitment of NHEJ factors to DNA double-stranded breaks (DSBs). These data reveal a mechanism where SIRT6 mediates a crosstalk between transcription and DNA repair machineries to promote DNA repair. SIRT6 functions in multiple pathways related to aging, and its novel function coordinating DNA repair and transcription is yet another way by which SIRT6 promotes genome stability and longevity.