Abstract
Ribosome biogenesis and protein synthesis are fundamental rate-limiting steps for cell growth and proliferation. The ribosomal proteins (RPs), comprising the structural parts of the ribosome, are essential for ribosome assembly and function. In addition to their canonical ribosomal functions, multiple RPs have extra-ribosomal functions including activation of p53-dependent or p53-independent pathways in response to stress, resulting in cell cycle arrest and apoptosis. Defects in ribosome biogenesis, translation, and the functions of individual RPs, including mutations in RPs have been linked to a diverse range of human congenital disorders termed ribosomopathies. Ribosomopathies are characterized by tissue-specific phenotypic abnormalities and higher cancer risk later in life. Recent discoveries of somatic mutations in RPs in multiple tumor types reinforce the connections between ribosomal defects and cancer. In this article, we review the most recent advances in understanding the molecular consequences of RP mutations and ribosomal defects in ribosomopathies and cancer. We particularly discuss the molecular basis of the transition from hypo- to hyper-proliferation in ribosomopathies with elevated cancer risk, a paradox termed “Dameshek’s riddle.” Furthermore, we review the current treatments for ribosomopathies and prospective therapies targeting ribosomal defects. We also highlight recent advances in ribosome stress-based cancer therapeutics. Importantly, insights into the mechanisms of resistance to therapies targeting ribosome biogenesis bring new perspectives into the molecular basis of cancer susceptibility in ribosomopathies and new clinical implications for cancer therapy.
Highlights
Cell growth and proliferation are two distinct but coupled biological processes that are directly dependent on the tight coordination of protein synthesis and metabolic activity
Ribosome biogenesis takes place within specialized subnuclear compartments known as the nucleoli[7,8] and depends on the coordinated regulation of the three DNA-dependent RNA polymerases (Pol I, Pol II, and Pol III), as well as the involvement of a plethora of transcription factors, small nucleolar RNAs and non-ribosomal proteins (RPs) that cooperatively promote the transcription, modification and processing of ribosomal RNA (rRNA), synthesis of RPs and ribosome assembly[2,9–12] (Fig. 1a)
This review focus on Diamond–Blackfan anemia (DBA) and Myelodysplastic syndrome (MDS) with chromosome 5q deletion (del(5q) MDS) in which RP mutations have been linked to the disease etiology (Table 1), and on diseases associated with mutations in other ribosome biogenesis factors including Shwachman-Diamond syndrome (SDS), X-linked-dyskeratosis congenita (XL-DC), cartilage–hair hypoplasia–anauxetic dysplasia (CHH-AD) and Treacher Collins Syndrome (TCS)
Summary
Ribosomal proteins and human diseases: molecular mechanisms and targeted therapy. Jian Kang[1,2], Natalie Brajanovski[1], Keefe T. We refer readers to other excellent reviews on mitochondrial RPs and their role in mitochondrial protein synthesis.[80,81] In addition to their structural and regulatory roles in the assembly of the ribosome, RPs perform other “moonlighting” extra-ribosomal functions including the regulation of cell growth, proliferation and differentiation, immune signaling, DNA repair and apoptosis. P53 activity is kept repressed by Mdm[2] via two complementary mechanisms: (i) Mdm[2] acts as an E3 ubiquitin ligase that directly transfers ubiquitin onto p53 thereby targeting it for 26S proteasomal degradation;[91,92] and (ii) the direct binding of Mdm[2] to the N-terminal domain of p53 inhibits the transcriptional activity of p53 by preventing its interaction with the Pol II transcription machinery.[93,94] This Mdm2-dependent surveillance of p53 activity is regulated by distinct and independent mechanisms to those involving replicative stress and the DNA damage response (DDR) where phosphorylation of either Mdm[2] or p53 prevents their interaction, leading to p53 stabilization.
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