Targeting Telomere Protein Destroys Cancer Cells

Inactivating a protein called mammalian Rad9 could make cancer cells easier to kill with ionizing radiation, according to recent research.

The investigators discovered that Rad9, previously thought to be a "watchman” that monitors for DNA damage, is in actuality a "repairman” that fixes hazardous breaks in the DNA double helix. They found Rad9 is mostly active in telomeres, the protective ends of chromosomes. Because of this new role, Rad9 has earned the investigators' interest as a possible target for cancer treatment--knocking out Rad9 would enhance the effectiveness of radiation treatments by making it easier for radiation to inflict lethal damage to a tumor's genetic material. Their study appears in the March 2006 issue of the journal Molecular and Cellular Biology.

"Our study suggests that if we could inactivate Rad9 in tumor cells, we would be able to kill them with a very low dose of radiation and gain a therapeutic advantage,” stated senior author Tej K. Pandita, Ph.D., associate professor of radiation oncology and a faculty member of the Siteman Cancer Center at Washington University School of Medicine (St. Louis, MO, USA).

The study demonstrated that Rad9 proteins interact with chromosomes' telomeres, which are distinctive structures at the ends of chromosomes that protect them from degradation or fusion. Particularly, Rad9 proteins were shown to interact with proteins called telomere-binding proteins. When the scientists inactivated Rad9 in human cells, they saw damage to chromosomes and end-to-end fusion at the telomeres. DNA damage and chromosomal fusion can interrupt the cell cycle and cause cell death. Because radiation treatments increase these incidents, loss of Rad9 in cancer cells could enhance the killing effect of radiation.

Earlier studies had suggested that Rad9 maintains cell-cycle checkpoint controls--researchers believed that the protein helped track DNA during replication and signaled the cell to stop its growth cycle if damage was detected. That role is not supported by this current study, and it has become evident that Rad9 directs the repair of DNA damage instead, according to Dr. Pandita.

"We saw that Rad9 stabilizes telomeres, and because we aren't yet sure how it does it, we will continue to study how Rad9 influences the telomere structure,” Dr. Pandita said. "We speculate that without Rad9, some of the other proteins associated with the telomeric structure become delocalized, exposing the DNA at the ends of chromosomes.”

In addition to being able to enhance radiosensitization of cancerous tissues by inactivating Rad9, the researchers would like to be able to identify individuals with mutations in Rad9 because such mutations could predispose a person to cancer. "If Rad9 isn't functioning properly in cells, it can lead to genomic instability and result in the malignant transformation of cells,” stated Dr. Pandita. "In fact, fusions at the telomeric ends of chromosomes like those seen in the absence of Rad9 appear frequently in tumor tissues.”

The study's results put Rad9 at a vital juncture: its function is crucial to the health of cells, and this makes it a major vulnerability to exploit for cancer therapy.



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