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Resolving R-loops for ribosomes
RNA/DNA structures called R-loops formed during gene transcription can inhibit the activity of RNA polymerase and alter gene expression. Jiang et al. found that the Microprocessor complex resolved R-loops formed during the transcription of ribosomal protein-encoding genes in a nutrient status–dependent manner. Ribosomal protein abundance was decreased in erythrocyte progenitor cells in mice deficient in the Microprocessor complex component Drosha, which depressed the synthesis of proteins critical for erythrocyte maturation such as the transcription factor Gata1. These mice showed defects in erythropoiesis that resembled anemias in humans caused by ribosome insufficiency or dysfunction. Nutrient deprivation induced the nuclear export of Drosha and its degradation in the cytoplasm, which suppressed protein synthesis. Thus, this pathway provides a mechanism for cells to tightly regulate the transcription of mRNAs encoding ribosome proteins and limit the energy cost incurred by protein synthesis when nutrients are scarce.
Abstract
Ribosome biogenesis in eukaryotes requires the coordinated production and assembly of 80 ribosomal proteins and four ribosomal RNAs (rRNAs), and its rate must be synchronized with cellular growth. Here, we showed that the Microprocessor complex, which mediates the first step of microRNA processing, potentiated the transcription of ribosomal protein genes by eliminating DNA/RNA hybrids known as R-loops. Nutrient deprivation triggered the nuclear export of Drosha, a key component of the Microprocessor complex, and its subsequent degradation by the E3 ubiquitin ligase Nedd4, thereby reducing ribosomal protein production and protein synthesis. In mouse erythroid progenitors, conditional deletion of Drosha led to the reduced production of ribosomal proteins, translational inhibition of the mRNA encoding the erythroid transcription factor Gata1, and impaired erythropoiesis. This phenotype mirrored the clinical presentation of human “ribosomopathies.” Thus, the Microprocessor complex plays a pivotal role in synchronizing protein synthesis capacity with cellular growth rate and is a potential drug target for anemias caused by ribosomal insufficiency.
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