SIRT7-dependent deacetylation of CDK9 activates RNA polymerase II transcription

Blank, Maximilian F.; Chen, Sifan; Poetz, Fabian; Schnölzer, Martina; Voit, Renate; Grummt, Ingrid

The present work extends these previous studies, aiming to decipher the molecular mechanisms underlying the role of SIRT7 in transcription activation. We found that a large fraction of the SIRT7 interactome depends on ongoing transcription and/or the presence of RNA. The N-terminal part of SIRT7 binds to RNA and mediates RNA-dependent interactions with SIRT7 target proteins. Consistent with SIRT7 function not being restricted to processes related to ribosome biogenesis, we show that SIRT7 is associated with Pol II and regulates transcription of snoRNAs and other Pol II genes. Mechanistically, SIRT7 promotes the release of P-TEFb from the inactive 7SK snRNP complex and deacetylates the P-TEFb component CDK9. Deacetylation by SIRT7 activates the kinase activity of CDK9, which phosphorylates the C-terminal domain (CTD) of Pol II and facilitates transcription elongation. The results reveal a novel function of SIRT7 outside the nucleolus, reinforcing its role as a key regulator of cellular homeostasis.