Professor Emeritus, Department of Cell Biology
Chanin Bldg., Room 413A
The ribosome is a molecular machine composed of 4 RNA molecules and 80 different proteins. The construction of a ribosome involves the integration of fundamental cellular processes: the transcription, processing, and folding of ribosomal RNA, the transcription, processing and translation of the mRNAs for ribosomal proteins, the assembly of the ribosomal proteins with the ribosomal RNAs, etc. In the yeast Saccharomyces cerevisiae, the synthesis of ribosomes consumes an extraordinary proportion of the cell's resources, accounting for >70% of all transcription, about 50% of all Pol II transcription initiation events, and >90% of all pre-mRNA splicing.
In mammalian cells the quantitative aspects of ribosome synthesis may be less substantial, though still important. However, mammalian cells monitor ribosome synthesis closely, and any evidence of problems with ribosome synthesis can bring on a process known as ‘nucleolar stress’, that leads to accumulation of p53, with subsequent cell cycle stalling, or ultimately apoptosis. Naturally, such a response provides strong selection for suppression of the p53 response. Such selection is inherently carcinogenic, and aberrations in ribosomal genes, such as haploinsufficiency for a ribosomal protein gene, often lead to cancer.
Ribosome Synthesis and Disease: On the basis of these considerations it is my contention that the massive amount of transcriptome data acquired from microarrays and modern sequencing has the potential to reveal far more about the role of aberrant ribosome synthesis in human disease. Therefore, we are learning and developing tools to mine such data, looking for unexpected relationships between the products of the 80 ribosomal protein (RP) genes, the 2000 RP pseudogenes, the 75 mitochondrial RP genes, and the ~200 genes encoding ribosome assembly factors in healthy and diseased cells. We have found that published conclusions (not the data) about RP mRNAs are wildly wrong. Nevertheless our analysis suggests an important role for translational control. Our analysis of alternative splicing of RP mRNAs finds a single strong case, but many other hints that are either ‘mistakes’ or intriguing variants. We shall see! In the near future, we will expand these analyses to include the mitochondrial RPs, since the role in human disease of mitochondrial defects is becoming increasingly apparent.