SIRT6 promotes transcription of a subset of NRF2 targets by mono-ADP-ribosylating BAF170.

Sarallah Rezazadeh, David Yang, Gregory Tombline, Matthew Simon, Sean P Regan, Andrei Seluanov, Vera Gorbunova

Nucleic acids research 2019 Sep 05

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SIRT6 is critical for activating transcription of Nuclear factor (erythroid-derived 2)-like 2 (NRF2) responsive genes during oxidative stress. However, while the mechanism of SIRT6-mediated silencing is well understood, the mechanism of SIRT6-mediated transcriptional activation is unknown. Here, we employed SIRT6 separation of function mutants to reveal that SIRT6 mono-ADP-ribosylation activity is required for transcriptional activation. We demonstrate that SIRT6 mono-ADP-ribosylation of BAF170, a subunit of BAF chromatin remodeling complex, is critical for activation of a subset of NRF2 responsive genes upon oxidative stress. We show that SIRT6 recruits BAF170 to enhancer region of the Heme oxygenase-1 locus and promotes recruitment of RNA polymerase II. Furthermore, SIRT6 mediates the formation of the active chromatin 10-kb loop at the HO-1 locus, which is absent in SIRT6 deficient tissue. These results provide a novel mechanism for SIRT6-mediated transcriptional activation, where SIRT6 mono-ADP-ribosylates and recruits chromatin remodeling proteins to mediate the formation of active chromatin loop. Published by Oxford University Press on behalf of Nucleic Acids Research 2019.

Citation

Sarallah Rezazadeh, David Yang, Gregory Tombline, Matthew Simon, Sean P Regan, Andrei Seluanov, Vera Gorbunova. SIRT6 promotes transcription of a subset of NRF2 targets by mono-ADP-ribosylating BAF170. Nucleic acids research. 2019 Sep 05;47(15):7914-7928