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Apr 1, 2014

Researchers Bid to Resolve Ribosomopathy Paradox

  • Ribosomopathies—disorders caused by the incorporation of faulty proteins in ribosomes—are paradoxical. In early life, they are characterized by the production of too few cells. Then, in middle age, they are characterized by the production of too many. For example, early on, ribosomopathies manifest as bone marrow failure and anemia. Later, in people who survive these conditions, ribosomopathies give rise to cancer.

    To explain the two faces of ribosomopathy, resesearchers at the University of Maryland, the University of Texas, and the University of Leuven in Belgium have outlined a sequence of molecular events. First, an inherited genetic mutation gives rise to faulty ribosomal machinery. Then, some additional change occurs. This change, possibly an additional mutation, causes the machinery to run relatively free of restraint.

    The loss of restraint is crucial to resolving the ribosomopathy paradox. Early on, an inherited mutation results in faulty ribosomes, which are held in check by the cell’s quality control mechanisms. These mechanisms eliminate mutant ribosomes, leaving a fairly small pool of translationally active ribosomes. Cells proliferate, but slowly. Then, in later life, when quality control is somehow compromised, cells proliferate more rapidly, but they generate faulty proteins. The cells themselves may be compromised.

    This model was proposed March 31 in the Proceedings of the National Academy of Sciences, in an article entitled “Bypass of the pre-60S ribosomal quality control as a pathway to oncogenesis.” In this article, the authors described their model system—a strain of yeast containing the most commonly identified ribosomal mutation in a potentially fast-moving form of leukemia known as T-cell acute lymphoblastic leukemia (T-ALL).

    “This mutation,” wrote the authors, “causes a late-stage 60S subunit maturation failure that targets mutant ribosomes for degradation.” Then, as degradation of ribosomes proceeds, the “hypoproliferation phenotype” emerges, and selective pressures build. That is, “cells select for suppressors of the ribosome biogenesis defect, allowing them to reestablish normal levels of ribosome production and cell proliferation.” In their studies with yeast, the researchers identified a couple of suppressors that compensated for proliferation and biogenesis defects without correcting the structural and biochemical defects caused by the original mutation.

    Whether by means of a suppressor mutation or an altered pattern of gene expression—or, possibly, both—defective ribosomes enter the translationally active pool, leading to the “destabilization of selected mRNAs and shortened telomeres.” Moreover, continued defective translation could lead to the onset of T-ALL. The researchers speculated that their findings could point to a "'selective-pressure'-based model of the connection between ribosomopathies and carcinogenesis."

    One of the study’s authors, Jonathan Dinman, Ph.D., a professor at the University of Maryland, likened ribosomopathy to the accumulation of manufacturing defects in cars. He began by saying that in the cellular assembly line, as in an automobile assembly line, many different parts are brought together to make a complex, fine-tuned, high-performance machine: “The assembly line contains quality control inspectors located at critical points in the process to ensure that machines with defective parts do not make it out of the factory and onto the roads.”

    “Imagine a scenario where the only supplier of a specific part produces a defective one,” Dr. Dinman continued. “If the inspectors do their jobs, very few new cars will reach the market. This scenario would put most car companies out of business—this is equivalent to bone marrow failure. In the meantime, the demand for new cars increases. This opens the door for an unscrupulous company to fire their inspectors and flood the market with ‘lemons.’ While good for the company’s bottom line in the short term, in the long term the increased rates of accidents and lawsuits wreak havoc.”

    In people, such havoc may correspond to cancer. “Although defects in the translational machinery have previously linked to cancer, the concept that somatic cells can acquire a defect in the ribosome machinery is relatively novel and there is currently little knowledge regarding the molecular mechanisms by which such a defect may promote a specific type of cancer.” To explore such mechanisms, the researchers are looking for suppressors in human cells. These suppressors may serve as targets for anticancer drugs.



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