Abstract
Bowen–Conradi syndrome (BCS) is a lethal autosomal recessive disorder caused by a D86G substitution in the protein, Essential for Mitotic Growth 1 (EMG1). EMG1 is essential for 18S rRNA maturation and 40S ribosome biogenesis in yeast, but no studies of its role in ribosome biogenesis have been done in mammals. To assess the effect of the EMG1 mutation on cell growth and ribosomal biogenesis in humans, we employed BCS patient cells. The D86G substitution did not interfere with EMG1 nucleolar localization. In BCS patient lymphoblasts, cells accumulated in G2/M, resulting in reduced proliferation rates; however, patient fibroblasts showed normal proliferation. The rate of 18S rRNA processing was consistently delayed in patient cells, although this did not lead to a difference in the levels of 40S ribosomes, or a change in protein synthesis rates. These results demonstrate that as in yeast, EMG1 in mammals has a role in ribosome biogenesis. The obvious phenotype in lymphoblasts compared to fibroblasts suggests a greater need for EMG1 in rapidly dividing cells. Tissue-specific effects have been seen in other ribosomal biogenesis disorders, and it seems likely that the impact of EMG1 deficiency would be larger in the rapidly proliferating cells of the developing embryo.
Highlights
Bowen–Conradi syndrome (BCS, MIM #211180) is a lethal autosomal recessive disorder common in the Hutterite population of the Canadian Prairies and the United States Great Plains
A reduction in levels of the ribosome biogenesis enzyme Emg1 causes a decrease in 18S rRNA levels with a corresponding accumulation of its immediate precursor in the rRNA processing pathway [7]. This lack of 18S rRNA leads to an imbalance between the large and small ribosomal subunits, which in turn causes a reduction in protein synthesis and cell proliferation rates [8]
We expected that since Essential for Mitotic Growth 1 (EMG1) levels are severely reduced in BCS patient lymphoblasts and fibroblasts, we would see a corresponding decrease in cell proliferation and protein synthesis rates due to a deficiency of small ribosomal subunits
Summary
Bowen–Conradi syndrome (BCS, MIM #211180) is a lethal autosomal recessive disorder common in the Hutterite population of the Canadian Prairies and the United States Great Plains. Other roles for Emg during ribosome biogenesis have been proposed, including recruitment of the ribosomal small subunit protein RPS19 to the maturing ribosome, and removal of snR57, the snoRNA component of the snoRNP responsible for the 2′-OH ribose methylation of G1570 in yeast 18S rRNA [21]. Most small subunit processome proteins are essential for cell survival [17,18,23], and depletion causes specific ribosome biogenesis deficiencies. Assuming similar functions for yeast and human EMG1, we hypothesized that the reduction in EMG1 protein levels seen in BCS patients would result in altered 18S rRNA processing, and deficient biogenesis of the small ribosomal subunit. We show that cell proliferation rates were significantly reduced in patient lymphoblasts concomitant with a cell cycle delay at G2/M, without detectably altering steady-state levels of the small subunit of the ribosome, 18S rRNA levels, or protein synthesis rates. Processing of 18S rRNA was slightly, but consistently, delayed in both lymphoblasts and fibroblasts from BCS patients
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