Ribosomes and growth regulation.

Ribosomes are responsible for protein synthesis in the cell and are essential for growth and cell division. Genetic defects that interfere with ribosome biogenesis reduce translation and growth and cause human diseases. Heterozygous mutation of many ribosomal protein genes causes Diamond-Blackfan Anemia, which is associated with early onset anemia, morphological defects, and cancer predisposition. Ribosomal protein genes are also haploinsufficient in the fruitfly Drosophila, where they cause reduced protein synthesis, slow growth and development, and morphological defects. Unexpectedly, these effects are found to have a transcriptional basis, that is, ribosomal protein mutations activate a transcriptional program which controls translation and the other effects. This project will determine how ribosome biogenesis defects cause human diseases and cancer by elucidating the molecular mechanisms of this transcriptional response in Drosophila, and exploiting mutations that prevent cells reacting to ribosomal protein mutations. The project will use ribosome profiling methods to define the hierarchy of steps at which translation of the genome into protein is altered and highlight those likely to be relevant to cancer, anemia, and morphology. The project will use gene modification approaches to define the specific roles of individual protein isoforms and domains in the effects of ribosome biogenesis defects. The project will explore what physiological and selective role is played by the cellular responses to ribosome biogenesis defects, and their contribution to promoting health and survival and preventing disease. The findings are anticipated to suggest approaches to prevent cancer and treat the ribosomopathy Diamond Blackfan Anemia.