Faulty ribosome biogenesis underlies the ribosomopathy alopecia, neurological defects, endocrinopathy (ANE) syndrome

Abstract

Most cells spend the vast majority of their energy making ribosomes, the machines that translate messenger RNA into protein. The ribosome is a tremendously elaborate machine comprising over 80 individual ribosomal proteins and four ribosomal RNAs. The biogenesis of these machines requires an additional 200 different factors. This amazing assembly feat is accomplished 30 times per second in a growing yeast cell (1) and 125 times per second in a growing human tissue culture cell (2). Given the complexity, frequency, and significance of the task, it is no wonder that human syndromes exist in which ribosome biogenesis is disrupted by a genetic mutation, such as the one described in PNAS (3). Fig. 1. ANE syndrome is a ribosomopathy characterized by alopecia and neurological and endocrine defects. The syndrome is caused by biallelic mutations in RBM28 that create greater than 50% loss of function. RBM28 encodes a nucleolar protein that supports the processing of ribosomal RNAs for inclusion in the 60S large ribosomal subunit. Ribosome biogenesis is a spatially organized process in cells. The genes encoding three of the ribosomal RNAs (18S, 5.8S, and 28S) are located in a specialized part of the nucleus known as the nucleolus. The nucleolus is where these RNAs are transcribed as a single transcript, which is then further processed and modified by a host of nucleolar factors that include exonucleases and endonucleases. Due to the demand for ribosomes, genes encoding the ribosomal RNAs are present in many copies that are simultaneously transcribed. Transcription of the ribosomal RNAs takes place via the specialized RNA polymerase I and RNA polymerase III, whereas genes encoding the ribosomal proteins are transcribed by RNA polymerase II, making ribosome biogenesis a process that requires the action of all three major nuclear RNA polymerases. Ribosomal proteins are translated in the cytoplasm and then … [↵][1]1Email: jeg{at}stowers.org. [1]: #xref-corresp-1-1