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SIRT7-dependent deacetylation of the U3-55k protein controls pre-rRNA processing [CLIP-Seq]

ABSTRACT: SIRT7 is an NAD+-dependent protein deacetylase with important roles in ribosome biogenesis and cell proliferation. Previous studies have established that SIRT7 is associated with RNA polymerase I, interacts with pre-rRNA and promotes rRNA synthesis. Here we show that SIRT7 is also associated with snoRNAs that are involved in pre-rRNA processing and rRNA maturation. Knockdown of SIRT7 impairs U3 snoRNA-dependent early cleavage steps that are necessary for generation of 18S rRNA. Mechanistically, SIRT7 deacetylates U3-55k, a core component of the U3 snoRNP complex, and reversible acetylation of U3-55k modulates the association of U3-55k with U3 snoRNA. Deacetylation by SIRT7 enhances U3-55k binding to U3 snoRNA, which is a prerequisite for pre-rRNA processing. Under stress conditions, SIRT7 is released from nucleoli, leading to hyperacetylation of U3-55k and attenuation of prerRNA processing. The results reveal a multifaceted role of SIRT7 in ribosome biogenesis, regulating both transcription and processing of rRNA.

ORGANISM(S): Homo sapiens

PROVIDER: GSE76578 | GEO | 2016/01/07

SECONDARY ACCESSION(S): PRJNA308081

REPOSITORIES: GEO

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Project description:Osteoarthritis (OA) is a chronic debilitating joint disease which is strongly associated with ageing. OA involves pathological cellular processes in all joint structures and affects articular cartilage integrity, leading to dysfunctional joint articulation. The biomolecular processes that catalyze the disturbances in the articular chondrocyte phenotype leading to OA are poorly understood, and it is expected that a comprehensive understanding of the avenues leading to catabolic changes and disruption of articular chondrocyte homeostasis will provide important cues for future treatments of the condition. Chondrocytes are specialized secretory cells with highly active protein translational machinery, enabling the synthesis and maintenance of the protein-rich cartilage extracellular matrix (ECM). Disturbances in chondrocyte protein translation in cartilage development and OA are connected to mTOR activity, ER stress, unfolded protein response (UPR)and CHOP-mediated apoptosis. These responses change the downstream translational activity of the biosynthesized ribosome. The assembled mammalian ribosome is built from ribosomal RNAs (rRNAs), together with more than 80 different protein subunits. At the heart of the ribosome, the 18S rRNA guides the decoding of the mRNA message, while an ancient ribozyme activity in the 28S rRNA forms the core of the peptidyltransferase center that polymerizes the amino acid sequence encoded by the mRNA into functional proteins. Post-transcriptional maturation of rRNAs is an integral part of the biosynthesis of ribosomes and ribonucleolytic processing of the major 47S rRNA precursor into mature 18S, 5.8S, and 28S rRNAs is rate limiting for ribosome biogenesis. The U3 small nucleolar RNA (snoRNA) is an evolutionarily highly conserved box C/D-class snoRNA which catalyzes the endoribonucleolytic processing of the 5’ external transcribed spacer (ETS) of the 47S pre-rRNA by base complementarity-guided pre-rRNA substrate recognition and plays a crucial role in the maturation of 18S rRNA. Although extensively studied in yeast, it was only recently demonstrated that U3 snoRNA is indispensable for rRNA maturation in human cells. Pathways controlling ribosome activity have previously been described in the regulation of chondrocyte homeostasis. We here now postulate that not only ribosome activity is involved in chondrocyte homeostasis, but that OA pathophysiological situations can also cause alterations in chondrocyte ribosome biogenesis with consequences for cellular protein translation. Since U3 snoRNA-driven rRNA production is rate-limiting in ribosome biogenesis, we hypothesized that the U3 snoRNA is critical for chondrocyte homeostasis. In this study we therefor aimed to determine whether OA pathophysiological conditions interact with chondrocyte U3 snoRNA levels, thereby influencing rRNA levels and chondrocyte translation capacity.

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SIRT7-dependent deacetylation of the U3-55k protein controls pre-rRNA processing [CLIP-Seq]

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