Ribosomes: Structure and Function

In order to understand ribosomopathies, a heterogeneous class of human diseases, it is better to first have a glimpse at the molecular machinery known as the ribosome. Structurally, the ribosome is mainly composed of ribosomal RNAs (rRNAs) and ribosomal proteins (RPs); its function is to perform the arduous task of decoding genomic DNA, a genetic information carrier, and converting the genetic codes into amino acids, the building blocks for proteins, in a process aptly known as translation. The ribosome thus plays an indispensible role in the production of all the proteins in our body - including the RPs necessary for its own function.

Although the primary function of the ribosome is to make proteins, more recent investigations have expanded its repertoire, adding two key facets of functionality. First, the proteins that comprise the ribosome do more than simply aid in translation. RPs have been found to regulate specific messages coming from the nucleus, essentially having a say in which messages are converted into proteins and which messages are ignored. Second, the individual RPs that constitute the ribosome are not static, but are highly dynamic both spatially and temporally. The ribosomal profile of one particular cell may widely differ from another cell in terms of developmental maturity and tissue specificity. With these pieces of knowledge in mind, we can turn our attention to understanding diseases that incur when the functionality of ribosomes is compromised.

Ribosomopathies: When Ribosomes Go Wrong

Apparently, ribosomopathies are pathologic conditions that result from dysfunctional ribosomes. However, the heterogeneous nature of ribosomal function translates to a heterogeneous class of diseases. The mechanisms of action and resulting clinical presentations and therapeutic options differ significantly between one ribosomopathy and another (Table 1). Because these diseases are caused by different ribosomal defects, their clinical features vary greatly. For example, pancreatic insufficiency is specific for Schwachman-Diamond syndrome (SDS), compared to the skin hyperpigmentation and pulmonary fibrosis found in X-linked dyskeratosis congenita (DKC). Nevertheless, their clinical features share some similarities. With the exception of Treacher Collins syndrome, each of the listed ribosomopathies is associated with blood abnormalities and an increased risk for cancer. Heterogeneity also occurs even within these two pathologic categories. Patients with Diamond-Blackfan Anemia (DBA), 5q-syndrome, or Cartilage hair hypoplasia (CHH) all face complications of anemia, but each disease carries a different cancer risk profile. Similarly, patients with either SDS or DC carry the risk for contracting AML, but only those with DC also suffer from solid tumors in the head and neck.  

With our incomplete understanding of how ribosomal failures lead to such variable pathologies comes the unfortunate reality that current therapies are only limited to symptomatic treatment with stem cell transplantation being potentially required in cases of bone marrow failure or blood cancers. Although a good progress has been made in identifying specific and defective RP-coding genes, there is still much to learn. Illustrating the molecular mechanisms governing the ribosome is the key to developing improved and targeted treatment regimens for all patients with ribosomopathies.

Dr Nguyan & Dr Lu are authors of the recently published paper Ribosomopathies: Mechanisms of Disease, available for download now in Clinical Medicine Insights: Blood Disorders.

share on