Characterization of the relationship between two RBM5 family members

Abstract

RNA binding proteins (RBPs) control all aspects of RNA metabolism, and a single RBP can have numerous downstream effects. Alterations to their expression and/or function can, therefore, have remarkable consequences. For instance, decreased levels of the RNA binding motif domain (RBM) protein RBM5 are associated with increased risk of a number of cancer types, and RBM10 mutations can be lethal. Although these consequences are quite severe, little is known regarding the range of processes and events influenced by these two homologous RBPs. In fact, previous RBM5 and RBM10 functional studies were largely focused only on their abilities to promote two processes; apoptosis and cell cycle arrest. Potentially by control of these processes, RBM5 and RBM10 were shown to influence one event: differentiation. The objectives of this study were to identify all cellular processes and events enriched by changes in RBM5 and/or RBM10 expression in a particular cultured cell line, and to determine the extent of functional overlap for RBM5 and RBM10 in these cells. Towards these goals, a list of RBM5 and RBM10 mRNA targets and differentially expressed genes was determined using next generation sequencing techniques. Our data suggest that RBM5 and RBM10 do influence a wide range of cellular processes and events. Although there is overlap in RBM5 and RBM10 mRNA targets and differentially expressed genes, these RBPs can have antagonistic functions; for example our data suggest that RBM5 prevents the transformed state, whereas RBM10 actually promotes it in an RBM5-null environment. Furthermore, we present a working model by which RBM5 may regulate RBM10’s protransformatory function. Finally, we demonstrate a relationship between RBM5 and RBM10 in non-transformed cells. The results presented herein provide insight not only into the roles and regulation of RBM5 and RBM10, but of RBPs in general. Taken together, the results presented in the four papers included in this thesis expand the knowledge base of RBM5 and RBM10, which provides insight into the disease states associated with their disrupted expression or function. Our findings are thus relevant to a wide range of scientific fields including molecular, developmental and cancer biology.