Grant: Operating Grant

The tRNA genes make molecules called tRNAs. tRNAs are important because they are essential for protein production. In general the tRNA genes are very active in rapidly growing cells. Most cancer cells, for example, grow rapidly and make tRNAs at a high rate. On the other hand, the slower growing cells from which such cancers develop make the tRNAs at a low rate. Because of these relationships, we are interested in understanding how the rate of tRNA synthesis is controlled. We study the regulation of tRNA synthesis in yeast, which is easy to manipulate experimentally and uses many of the growth control methods that are used by human cells. We recently discovered a new mechanism for controlling the tRNA genes. This mechanism turns off tRNA genes if the cell is having difficulty copying its DNA. Most importantly, this mechanism becomes highly active when DNA copying is inhibited by some cancer-causing chemicals. Why turn off the tRNA genes when DNA copying is perturbed? The reason is likely related to the fact that tRNA genes themselves interfere with DNA copying when they are active, i.e. how better to improve DNA copying than to turn off natural barriers to copying (i.e. turn off the tRNA genes)? Because of the implications of our findings for cancer, we are interested in exactly how the cell turns off the tRNA genes when DNA copying is perturbed. Cells can turn off the tRNA genes by many different methods. Our discovery of how they do it when treated with cancer-causing chemicals is particularly exciting: they actually use regulatory proteins that are frequently mutated in cancer cells. We now propose to determine the molecular mechanism by which these regulatory proteins turn off tRNA genes. In the longer term, our discoveries concerning the control of tRNA synthesis in yeast are expected to guide studies aimed at understanding how the activity of these genes is controlled in human cells, particularly during the development of cancer.