SIRT7-dependent deacetylation of CDK9 activates RNA polymerase II transcription

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

Although SIRT7 has emerged as a critical regulator of metabolic health and stress response, which promotes survival in times of adversity, it is the least understood member of the human sirtuin family. This is to a large extent due to its low enzymatic activity in vitro and the few molecular targets identified so far. Global proteomic studies have identified numerous SIRT7-associated proteins, most of them serving functions in transcription, ribosome biogenesis and translation (14) (15) (16) . We have previously shown that SIRT7 is released from nucleoli in response to transcriptional, metabolic or osmotic stress, leading to hyperacetylation of PAF53 and the U3-55k protein, hyperacetylation compromising rDNA transcription and pre-rRNA processing (12, 13) . Given the vital role of SIRT7 in cellular homeostasis, it is not surprising that SIRT7 function is not restricted to pre-rRNA synthesis and processing. Our mass spectrometric analyses revealed many nuclear SIRT7-associated proteins with functions in RNA metabolism, chromatin structure, nucleocytoplasmic transport and Pol II transcription, emphasizing that SIRT7 serves important roles outside the nucleolus. Previous studies have shown that SIRT7 deacetylates H3K18 in a gene-specific context, and selective hypoacetylation of H3K18Ac is necessary for essential features of cancer cells, including anchorage-independent growth and escape from contact inhibition (11) . SIRT7 was also found to interact with proteins that are associated with the Pol II and the Pol III transcription machinery (14, 16) . Consistent with SIRT7 interacting with TFIIIC, knockdown of SIRT7 led to decreased levels of tRNAs, indicating that the regulatory impact of SIRT7 is not restricted to Pol I transcription but affects transcription by all three classes of nuclear RNA polymerases.