Molecular mechanisms of eukaryotic ribosome assembly

Understanding how the acquisition of a genetic mutation by a single cell drives a cancer by outcompeting its normal healthy cell counterparts is a key question in cancer biology. The genetic disorder Shwachman-Diamond syndrome (SDS) is an excellent model with which to address this question as individuals affected by the disorder have an increased propensity to develop blood cancers and the initiating genetic lesions are known. MRC-supported work in my lab defined the primary defect in SDS as impaired assembly of ribosomes, molecular nanomachines that make all the proteins in our cells. However, the basic mechanisms of ribosome assembly and how defects in this process promote cancer remain poorly understood. These are important questions, as mutations in ribosomal protein genes are now recognised as a common vulnerability in human cancers. However, there are two major barriers to progress in the field. The first is the lack of high-resolution structures of native human 60S ribosome assembly intermediates, which are highly dynamic and often transient. The second barrier is the inherent difficulty in tracking blood stem cell clones in vivo in human disease states. To overcome these obstacles, we will systematically determine the structures of key native 60S ribosomal subunit maturation intermediates using the latest imaging technologies. Furthermore, we will use acquired mutations in blood stem cells as an endogenous barcoding tool to determine how defects in ribosome assembly promote the development of cancer by outcompeting their normal counterparts.