Abstract
Author SummaryRibosomes are the extremely complex cellular machines responsible for constructing new proteins. In eukaryotic cells, such as yeast, each ribosome contains more than 80 protein or RNA components. These complex machines must themselves be assembled by an even more complex machinery spanning multiple cellular compartments and involving perhaps 200 components in an ordered series of processing events, resulting in delivery of the two halves of the mature ribosome, the 40S and 60S components, to the cytoplasm. The ribosome biogenesis machinery has been only partially characterized, and many lines of evidence suggest that there are additional components that are still unknown. We employed an emerging computational technique called network-guided genetics to identify new candidate genes for this pathway. We then tested the candidates in a battery of experimental assays to determine what roles the genes might play in the biogenesis of ribosomes. This approach proved an efficient route to the discovery of new genes involved in ribosome biogenesis, significantly extending our understanding of a universally conserved eukaryotic process.
Highlights
In eukaryotic cells, the synthesis of ribosomes is a complex process involving several hundred genes whose functions span transcription of precursor ribosomal ribonucleic acids, processing of pre-rRNAs, assembly of ribosomal proteins (r-proteins) with pre-rRNAs, and nuclear export of the ribosomal particles [1,2,3,4,5,6]
We constructed a computational predictor of ribosome biogenesis genes based on analysis of functional genomics, proteomics, and comparative genomics datasets that had been combined into a probabilistic gene network [21] covering about 95% of yeast proteome (Figure 1A)
This network employs a probabilistic scoring scheme to quantitatively integrate heterogeneous functional genomic and proteomic datasets, including mRNA-expression data across different conditions, protein-protein interaction datasets derived from literature curation, high-throughput yeast two-hybrid assay, affinity purification coupled with mass spectrometry, genetic interaction data, and in silico interaction datasets [21]
Summary
The synthesis of ribosomes is a complex process involving several hundred genes whose functions span transcription of precursor ribosomal ribonucleic acids (prerRNAs), processing of pre-rRNAs, assembly of ribosomal proteins (r-proteins) with pre-rRNAs, and nuclear export of the ribosomal particles [1,2,3,4,5,6]. Ribosome biogenesis is an essential process, with mutations of ribosome biogenesis genes either causing lethality or increasing susceptibility to cancer—e.g., bone marrow failure and leukemia [7] or breast cancer [8]. This pathway has been extensively studied over the past 30–40 y, and a broad picture of the major events is known for the yeast Saccharomyces cerevisiae. The mature small subunit contains 32 proteins and 18S rRNA, while the large subunit contains 46 proteins and three rRNAs: 5.8S, 25S, both derived from the 35S precursor, and 5S, which is transcribed separately by RNA polymerase III
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