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

Abstract

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.

The Roles of Histone Deacetylases and Their Inhibitors in Cancer Therapy

“…HDACs participate in the crosstalk between RNAP2 C-terminal domain acetylation and phosphorylation (Wang et al, 2009;Blank et al, 2017;Ali et al, 2019). SIRT6 recruits and mono-ADP-ribosylates switch/sucrose non-fermenting (SWI/SNF) related, matrix associated, actin dependent regulator of chromatin subfamily c member 2 (SMARCC2/BAF170) to form active chromatin at the enhancer of heme oxygenase-1, which subsequently recruits RNAP2 (Rezazadeh et al, 2019). SIRT6 can also bind p53 to effectively recruit RNAP2 to local promoters (Li et al, 2018).…”

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“…Chromatin immunoprecipitation assay was performed as described earlier (Rezazadeh et al, 2019). The immune complexes were captured using protein A −Sepharose beads.…”