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Seminars and Colloquia


SIRT7-dependent deacetylation of fibrillarin controls histone H2A methylation and rRNA synthesis during the cell cycle 
Fri, Jan 25, 2019,   11:30 AM to 12:30 PM at Seminar Room 34, 2nd Floor, Main Building

Dr. Aishwarya Iyer-Bierhoff
Molecular Biology of the Cell II, German Cancer Research Centre, DKFZ-ZMBH Alliance, Heidelberg, Germany


Ribosome biogenesis is the major biosynthetic task of the cell, requiring coordinated regulation of several processes to maintain cellular homeostasis. Recent studies have implicated ribosome biogenesis in aging as well as stem cell homeostasis and development. Synthesis of the RNA components of ribosomes (rRNA) is mediated by RNA polymerase I (Pol I) in the nucleolus. As Pol I transcription is the first and limiting step of ribosome biogenesis, it is tightly controlled according to cell growth and proliferation. Moreover, rRNA synthesis needs to be coordinated with modification and processing of the nascent pre-rRNA to yield mature rRNAs. The methyltransferase Fibrillarin (FBL) exerts two functions in rRNA biogenesis, catalyzing 2´-O methylation of pre-rRNA and methylating nucleolar histone H2A at glutamine 104 (H2AQ104). H2AQ104 methylation positively correlates with transcription of rRNA genes, however, the mechanisms that regulate FBL-directed RNA and histone methylation are largely unexplored.

The aim of this study was to decipher how post-translational modifications of FBL impact its dual substrate specificity. We found that FBL is acetylated at several lysine residues by CBP and deacetylated by SIRT7 in an NAD+-dependent manner. Surprisingly, acetylation of FBL did not affect rRNA methylation as revealed by RiboMeth-seq. However, using quantitative immunofluorescence we found that FBL acetylation impairs H2AQ104 methylation. Mechanistically, we show that hyperacetylation of FBL impairs the interaction with H2A and chromatin, thereby compromising H2AQ104 methylation and attenuating Pol I transcription. In line with shutdown of rRNA synthesis at the onset of mitosis, the interaction between SIRT7 and FBL is disrupted, leading to hyperacetylation of FBL and concomitant loss of H2AQ104 methylation. This reinforcement of transcriptional inhibition is released upon mitotic exit, where SIRT7-FBL interaction, FBL hypoacetylation and H2AQ104 methylation are restored. Together, the results reveal that SIRT7-dependent deacetylation impacts nucleolar activity by a FBL-driven circuitry that regulates Pol I transcription in a cell cycle-specific manner.