SIRT7-Dependent Deacetylation of Fibrillarin Controls Histone H2A Methylation and rRNA Synthesis during the Cell Cycle

摘要

Fibrillarin (FBL) is a dual-function nucleolar proteinthat catalyzes 20-O methylation of pre-rRNA andmethylation of histone H2A at glutamine 104(H2AQ104me). The mechanisms that regulate FBLactivity are unexplored. Here, we show that FBL isacetylated at several lysine residues by the acetyltransferaseCBP and deacetylated by SIRT7. Whilereversible acetylation does not impact FBL-mediatedpre-rRNA methylation, hyperacetylation impairsthe interaction of FBL with histone H2A and chromatin,thereby compromising H2AQ104 methylation(H2AQ104me) and rDNA transcription. SIRT7-dependentdeacetylation of FBL ensures H2AQ104meand high levels of rRNA synthesis during interphase.At the onset of mitosis, nucleolar disassembly isaccompanied by hyperacetylation of FBL, loss ofH2AQ104me, and repression of polymerase I (Pol I)transcription. Overexpression of an acetylation-deficient,but not an acetylation-mimicking, FBL mutantrestores H2AQ104me and transcriptional activity.The results reveal that SIRT7-dependent deacetylationimpacts nucleolar activity by an FBL-driven circuitrythat mediates cell-cycle-dependent fluctuationof rDNA transcription.