Oncologists could gain therapeutic advantage by targeting telomere proteinInactivating a protein called mammalian Rad9 could make cancer cells easier to kill with ionizing radiation, according to research at Washington University School of Medicine in St. Louis.
The researchers found that Rad9, previously considered a "watchman" that checks for DNA damage, is actually a "repairman" that fixes dangerous breaks in the DNA double helix. They found Rad9 is especially active in telomeres, the protective ends of chromosomes.
Because of this new role, Rad9 has gained the researchers' interest as a potential target for cancer therapy -- knocking out Rad9 would enhance the power of radiation treatments by making it easier for radiation to inflict fatal damage to a tumor's genetic material. Their study appears in the March issue of the journal Molecular and Cellular Biology, which is now available online.
"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," says senior author Tej K. Pandita, Ph.D., associate professor of radiation oncology and on the faculty of the Siteman Cancer Center at Washington University School of Medicine and Barnes-Jewish Hospital.
The study revealed that Rad9 proteins interact with chromosomes' telomeres, which are special structures at the ends of chromosomes that protect them from fusion or degradation. Specifically, 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 telomeres. DNA damage and chromosomal fusion can disrupt 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.
Previous research had suggested that Rad9 maintains cell cycle checkpoint controls--scientists thought that the protein helped monitor DNA during replication and signaled the cell to stop its growth cycle if damage was detected. That role is not supported by this current research, and it has become evident that Rad9 directs the repair of DNA damage instead, according to 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," Pandita says. "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 people 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," Pandita says. "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 findings place Rad9 at an important juncture: its function is vital to the health of cells, and this makes it a key vulnerability to exploit for cancer therapy.
Pandita RK, Sharma GG, Laszlo A, Hopkins KM, Davey S, Chakhparonian M, Gupta A, Wellinger RJ, Zhang J, Powell SN, Roti Roti JL, Lieberman HB, Pandita TK. Mammalian Rad9 plays a role in telomere stability, S- and G2-phase specific cell survival and homologous recombinational repair. Molecular and Cellular Biology March 2006;26(5):1850-1864.
Funding from the National Institutes of Health, Department of Defense, Ataxia-Telangiectasia Children's Society, the Canadian Cancer Society and the Department of Radiation Oncology at Washington University School of Medicine in St. Louis supported this research.
Washington University School of Medicine's full-time and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked third in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.
Siteman Cancer Center is the only NCI-designated Comprehensive Cancer Center within a 200-mile radius of St. Louis. Siteman Cancer Center is composed of the combined cancer research and treatment programs of Barnes-Jewish Hospital and Washington University School of Medicine.
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