SIRT7-dependent deacetylation of CDK9 activates RNA polymerase II transcription

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

Studies over the past decade have shown that sirtuins, members of a phylogenetically conserved protein family that shares homology to the budding yeast silencing factor Sir2 (silent information regulator), affect a broad range of cellular functions encompassing cellular stress resistance, genomic stability, energy metabolism and tumorigenesis. The seven mammalian sirtuins, denoted SIRT1-SIRT7, have distinct cellular locations and target multiple substrates. By utilizing NAD + as cofactor, sirtuins act either as deacety-lases or ADP-ribosyltransferases, and have emerged as key metabolic sensors that link environmental signals to metabolic homeostasis and stress response. SIRT7 is enriched in nucleoli, where it promotes cell growth and proliferation by driving rDNA transcription and ribosome biogenesis (1) . SIRT7 expression correlates with cell growth, being high in metabolically active cells, and low or even absent in non-proliferating cells (1) (2) (3) (4) . In epithelial prostate carcinomas, high SIRT7 levels are associated with aggressive cancer phenotypes, metastatic disease and poor patient prognosis (5) . High expression of SIRT7 is steadily propelling cells towards an oncogenic status. Depletion of SIRT7 or overexpression of a catalytically inactive point mutant leads to decreased cell proliferation, induction of apoptosis and reduced tumor growth (6) . SIRT7-knockout mice suffer from increased embryonic lethality, reduced stress resistance, inflammatory cardiomyopathy and premature aging (7) (8) (9) (10) . Moreover, SIRT7 catalyzes deacetylation of lysine 18 at histone H3 (H3K18ac), a biomarker of aggressive tumors. Hypoacetylation of H3K18 compromises transcription of genes that are linked to tumor suppression and facilitates DNA repair (10, 11) .