The ribosome complex is essential for mRNA translation and generation of the intricate array of proteins necessary for life. Increased ribosomes are a hallmark of cancer, while deficiency underlies congenital ribosomopathies. In a famous conundrum first posed by William Dameshek in 1967 and unsolved since, ribosomopathy patients transition from hypo-proliferation based symptoms (stunted growth/anaemia) to, paradoxically, experiencing hyper-proliferation and elevated cancer risk later in life.
Toward a solution to this riddle, our genetic models provide the first demonstration that ribosomal protein (RP) depletion can directly drive tissue overgrowth. Knockdown (KD) of Drosophila RpS19a within the hematopoietic compartment not only results in stem and progenitor cell loss but, concurrently, drives tissue overgrowth. We further demonstrate RpS19a KD results in ribosome heterogeneity and an altered translatome. In addition to upregulated growth promoting genes (e.g. Ras), we observe increased translation of the ribosomal RNA (rRNA) small subunit methyltransferase NEP1.
Although rRNA undergoes numerous modifications, contribution to normal ribosome function during development and significance for disease are poorly understood. NEP1 has been implicated in facilitating 40S assembly and 80S stability via methylation of 18S rRNA, and human NEP1 mutations cause the ribosomopathy Bowen-Conradi syndrome, which is associated with developmental defects, growth failure, and infantile death. Significantly, co-KD of NEP1 suppresses the RpS19a KD overgrowth phenotype and, moreover, NEP1 KD significantly decreases methylation of the 18S rRNA residue (Ψ1,279) implicated in ribosome assembly. Taken together, our exciting findings indicate that increased translation of NEP1, by heterogeneous RpS19a KD ribosomes, enables assembly of pro-proliferative “onco-ribosomes” to drive hematopoietic compartment overgrowth.