Study sheds light on cancer susceptibility and disease involving bone-marrow failure

Defective protein production can occur in cells even when the genes controlling those proteins are normal, according to a new study to be published May 12 in Science.

The Fox Chase Cancer Center research sheds light on how genetic defects affecting the control of protein synthesis within cells can increase susceptibility to cancer and other human diseases.

Directed by molecular biologist Davide Ruggero, Ph.D., of Fox Chase Cancer Center's human genetics program, the study attributed the protein defects to a critical glitch in the protein assembly line of ribosomes. This highlights the importance of proteomic research analyzing proteins.

"While defects in a number of genes are known to lead to cancer and disease, this opens up a new avenue of research," Ruggero said. "The DNA may be fine, but now we see another means by which the product it encodes can become defective."

Until now, little has been known about how disease may result from abnormal ribosomes--the protein factories of cells, which use RNA to translate the DNA blueprint into functional proteins. Ruggero's laboratory focuses on understanding control of ribosome activity and how disruptions in RNA translation predispose people to cancer.

His new study shows that specific defects in RNA translation underlie a progressive disease called dyskeratosis congenita. It involves multiple organ systems and includes premature aging and increased susceptibility to cancer. The disease results from a gene mutation, Dkc1, that affects ribosome function.

Dyskeratosis congenita involves abnormal bone marrow leading to anemia, immune deficiency and infections; increased risk of various cancers, including lymphoma; and, starting as early as age 10, abnormalities of skin, nails and mucous membranes that resemble premature aging syndromes. The majority of patients are male.

The Fox Chase researchers used a variety of approaches to study the Dkc1 mutation in cells from humans with dyskeratosis congenita and in a genetically altered mouse model. Ruggero had previously developed this model, which faithfully recapitulates the human disease in mice.

The scientists found a decrease in production of certain proteins due to a specific defect in RNA translation that depends on a sequence called internal ribosome entry site (IRES). This particular sequence occurs in only some of the messenger RNAs that translate the DNA code into proteins.

"One of these proteins with decreased levels is governed by a gene, p27, that normally works to suppress tumors," Ruggero pointed out. "This could be a key explanation for the increased tumor susceptibility seen in patients with dyskeratosis congenita.

"Two other proteins found in the study, XIAP and Bcl-xL, are involved in regulating the normal dying off of cells, a process called programmed cell death or apoptosis. These particular proteins help cells survive during stress conditions, so a decrease in their levels could be important in explaining the high death rate of blood stem cells that leads to bone-marrow failure in patients." The proteins Ruggero's new research identifies in connection with blood stem-cell depletion may also provide potential targets for developing new treatments for dyskeratosis congenita.

According to Ruggero, one long-term goal "is to see if we can apply our knowledge of protein synthesis control to the discovery of therapeutic agents that target the translational machinery in cancer cells and human disease."

Ruggero's co-authors include Andrew Yoon, a former scientific technician now attending medical school; postdoctoral associates Guang Peng, Ph.D., Yves Brandenburg, Ph.D., and Ornella Zollo, Ph.D., and scientific technician Wei Xu, all of Fox Chase, plus Eduardo Rego, M.D., Ph.D., of the Center for Cell-Based Therapy, FUNDHERP, University of Sao Paulo, Brazil.