Ribosomopathies are a collection of diseases caused by mutations in the structural proteins of the ribosome or in proteins that facilitate ribosome biogenesis. It is widely held that the developmental abnormalities that characterize ribosomopathies result from a generalized defect in ribosome biogenesis or function. In contrast to this view, we postulate that ribosomal proteins (RP) have the capacity to bind cellular RNAs outside the context of the ribosome, and that some human diseases are in fact caused by disruption of such distinct, extra-ribosomal functions. In support of this hypothesis, we have identified a paralogous pair of RNA-binding RP, Rpl22 and its paralog Rpl22-Like1 (Like1), that are dispensable for both the biogenesis and function of ribosomes, yet perform critical regulatory roles in hematopoiesis. Furthermore, despite their high degree of homology (>70% identical in amino acid sequence), we demonstrate that Rpl22 and Like1 perform distinct functions, i.e., a p53-dependent role in development of ?T lymphocytes and a Smad1-dependent role in driving hematopoietic stem cell (HSC) emergence, respectively. Importantly, not only do Rpl22 and Like1 perform distinct functions, but those functions are also mutually antagonistic. Indeed, the block in HSC emergence caused by knockdown of Like1 is rescued by eliminating Rpl22. The fact that the RNA binding helices of Rpl22 and Like1 are identical suggests that these proteins bind largely overlapping sets of RNA targets but have different effects on the activities of those targets. Thus, we now seek to understand how these highly homologous RP perform antagonistic functions that are critical at distinct stages of hematopoiesis. We will do so according to three aims: 1) To determine how systemic loss of Rpl22 causes a selective arrest of developing T cells. 2) To elucidate the basis for the antagonistic functions of Rpl22 and Like1. 3) To understand how the antagonistic balance of Rpl22 and Like1 controls HSC emergence by regulating Smad1.
Insights into how the antagonistic functions of Rpl22 and Like1 control hematopoiesis are quite clinically relevant, since our analysis suggests that dysregulation of these proteins leads to pathology. Specifically, dominance of Rpl22 over Like1 is associated with anemia in model organisms, while dominance of Like1 over Rpl22 appears to promote transformation. Like1 dominance occurs in T-acute lymphoblastic leukemia, myelodyslastic syndromes, and acute myelogenous leukemia.
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