Grant: Project Grant

The human body is composed of trillions of cells, the longevity of which depends on the balance between forces that promote or stall growth. On the one hand, early cell stalling is known as senescence, and it can lead to premature cellular aging if kept unchecked. On the other hand, uncontrolled cell growth can lead to cancer. Critical to the cell's ability to strike the right balance between growth and senescence are highly repetitive DNA regions known as ribosomal DNA (rDNA) repeats. These rDNA repeats harbor genes from which ribosomal RNA (rRNA) is produced. rRNA production is critical to cell growth. In contrast, DNA damage within rDNA repeats triggers premature senescence. So, the rDNA repeats are like a two-edged sword. How cells strike the right balance between the impact of rDNA on growth and senescence is unclear. Here, we pursue new findings suggesting that a novel network of proteins localizes to poorly understood spacers within rDNA repeats to optimize protein production and growth while limiting DNA damage and cell senescence. This network includes the breast and ovarian cancer tumor suppressor BRCA1 and several proteins collectively termed RNX. We have two main aims. First, we will study how this protein network allows cells to ensure the benefits while limiting the potentially harmful effects of the two-edged sword that is rDNA. Second, we will control this network to turn rDNA into a cancer-fighting weapon that we can use on-demand to block growth and increase senescence and death only in breast cancer cells. So, this project will uncover critical health-related knowledge on the balance between cell growth and senescence while revealing how to exploit this information to combat deadly human diseases, thereby improving the health and extending the life of Canadians.