Grant: Operating Grant - PA: Genetics (Bridge Funding: Research Priorities)

Ribosomes are essential biological machines that assemble the cell's proteins. The nucleolus is a dynamic structure in the nucleus that forms around the ribosomal (r)DNA genes that encode the large rRNA molecules that form the ribosome's core. As cells need many ribosomes, our genome contains ~300 copies of the rDNA gene in several dense clusters, which are extensively used to produce new rRNA. Their repetitive sequences and constant use make rDNA genes particularly susceptible to potentially mutation-inducing damage. Insufficient rDNA maintenance and repair can have profound effects on the human body, as the loss of rDNA copies and abnormal increases and decreases in ribosome generation affect organ development and have been observed in various cancers and developmental diseases. When rDNA is damaged, it is silenced to avoid generating defective ribosomes, and the nucleolus reorganizes, forming nucleolar caps that segregate the damaged rDNA and act as sites for its repair. Once repaired, the cap disappears, and the rDNA is once again used to make ribosomes. As the rDNA genes are among the most rearranged regions in human cancer genomes, promoting their repair could be a good therapeutic strategy. However, how rDNA repair and maintenance are regulated to ensure proper ribosome generation remains unclear. We recently identified previously unknown proteins with roles in rDNA repair. In this 5-year Project Grant, we will examine their recruitment to the nucleolar caps, protein interactions, and functions in the silencing, segregation, repair, and reactivation of rDNA in human cells. This will provide much-needed insight into how cells maintain their rDNA-and consequently, their genome-and prevent carcinogenesis, and uncover new targets for future cancer treatments.