Ribosomes and Growth Regulation

Ribosomes are responsible for protein synthesis and therefore necessary for the growth of all organs, in both normal development and in disease conditions such as cancer or cardiac hypertrophy. A number of congenital conditions, collectively termed ribosomopathies, result from defects in components of the ribosome or affect its biosynthesis. It is unclear why ribosomopathies have such distinct effects from one another, and it is unclear why mutations in ribosomal genes can cause cancer, since they are required for growth. Reducing the number of ribosomal genes reduces growth rate but surprisingly this has been found to be mainly due to the activation of a new, previously unstudied gene that is believed to encode a transcription factor. To understand how growth is affected, the target genes of this new transcription factor will be identified using a combination of genetic and molecular genetic studies that are possible in the fruitfly. To understand how the new pathway responds to ribosomal protein gene copy number, the DNA sequences that react to such changes will be mapped and characterized. The effect of ribosomal protein gene copy changes on the number of ribosomes, and on the accumulation of their assembly intermediates will be determined to indicate how gene expression is most likely affected. To explore what advantage might accrue from a pathway that slows growth and development, the implications for cell competition, the maintenance of cell size, and for organismal longevity, resistance to genome damage, and body symmetry will be assessed. Given that ribosomes are essential components of all cells, the results of these basic studies are likely to improve understanding of growth in all organs, and diseases that affect growth including cancer, heart disease, and ribosomopathies.