RNA Processing and Ribosome Biogenesis in Bone Marrow Failure Disorders

Abstract

Bone marrow failure disorders (BMFDs), which are characterized by an early pro-apoptotic phase which results in faulty hematopoiesis and anemia, more often than not progress to outright acute myelogenous leukemia (AML). Recent findings have indicated that most if not all of these disorders have a very significant RNA processing component to their pathology. This review aims to highlight some of normal processes of RNA metabolism that have been recently demonstrated to be altered in BMFDs.

Signal Transduction in Ribosome Biogenesis: A Recipe to Avoid Disaster

“…Ribosome biogenesis is a highly dynamic process in which transcription of the runes, processing/modification of the runes, association of ribosomal proteins (RPs) to the pre-runes, proper folding of the pre-runes, and transport of the maturing ribosomal subunits to the cytoplasm are all combined [2,5,6]. In addition to the RPs that represent the structural component of the ribosome, over 200 other non-ribosomal proteins and 75 snoRNAs are required for ribosome biogenesis.…”

“…In addition to the RPs that represent the structural component of the ribosome, over 200 other non-ribosomal proteins and 75 snoRNAs are required for ribosome biogenesis. The final product is a functional ribosome, which, in eukaryotes, consists of 40S and 60S subunits that contain 4 species of processed ribosomal RNAs (18S, 28S, 5.8S, and 5S) and 79 ribosomal proteins (RPs) [2,5,6,7]. The mature 40S subunit consists of 18S rRNA and 33 RPs, while the 60S subunit consists of 28S, 5.8S, and 5S runes and 43 RPs.…”

“…The mRNAs encoding the RPs are processed and transported to the cytoplasm for translation. RNA splicing of these transcripts also produces the scaRNAs and snoRNAs later needed for the formation of diverse heterogeneous ribonucleoprotein (hnRNP) complexes, C/D snoRNPs, and H/ACA snoRNPs that function in mRNA splicing and rRNA modification/maturation (Figure 1) [2,12]. Alternative splicing of RP transcripts also produces “pseudogenes” that regulate the expression/accumulation of RPs (see section on RNA editing and splicing) [13].…”

“…Two of the first RPs to associate with the pre-rRNA at the 5′-end are RPS7 and RPS24, which are required to initiate processing and cleavage of the pre-rRNA at the 5′-external transcribed spacer (ETS) (Figure 1). The initial binding of the RPSs and the processing at the 5’-ETS, as well as modifications of the rRNA by ribose methylases (C/D box snoRNPs) and polyuridylases (H/ACA box snoRNPs), energetically favors an rRNA structure that forms a platform for the next round of RPs to associate [2,5,6]. At the same time that processing of the 5′-end of the 18S rRNA is being conducted, association of RPS17 and RPS19 facilitate the processing and cleavage at the 3′-end of the 18S rRNA within the internal transcribed sequence (ITS1), liberating the assembling 40S subunit from the 60S subunit [2,5,6].…”

“…Mutations in any of the necessary proteins or alterations at practically any of the maturation steps can result in dire consequences to the organism, depending on both the penetrance of the alteration and the tissue involved. Thus, ribosome biogenesis is highly regulated with diverse checkpoints to limit the production of altered ribosomes [1,2].…”