February 9, 2009

New Telomerase Protein Discovered

Blue chromosomes with white pinpoints at ends. The 46 human chromosomes, shown in blue, with telomeres appearing as white pinpoints.Hesed M. Padilla-Nash and Thomas Ried, NCI

Scientists have discovered a novel part of the telomerase enzyme that helps it reach the ends of chromosomes, where it adds protective DNA sequences called telomeres. The finding suggests a promising new target for anti-tumor therapies.

Telomeres are protein-DNA complexes that cap the ends of chromosomes, the structures that contain our DNA. Telomeres prevent chromosomes from unraveling and keep the ends of chromosomes from attaching to each other, which can contribute to cancer.

Telomeres also act to limit the number of times a cell can divide. Before cells divide, they must copy all their DNA so the resulting cells have the same amount of genetic material. However, the cell's genetic machinery can't copy the DNA all the way to the end tips, so telomeres gradually shorten with each cell division. When the telomeres become too short, the cell stops dividing or dies.

Telomerase is the enzyme responsible for making telomeres. It's usually not produced in normal adult cells. Rather, it's expressed in cells such as embryonic cells, adult stem cells and immune cells, which are all responsible for producing other more specialized cells. In 80-90% of cancers, telomerase is reactivated—a hallmark of malignant cell transformation—enabling the cells to maintain long telomeres and divide indefinitely. That's what makes telomerase an attractive target for new cancer-fighting therapies.

Several components of the active telomerase enzyme have been identified, but the enzyme's large size suggests there are other unknown components. Unfortunately, progress has been limited by telomerase's small amounts and large size. In the new study, a team led by Dr. Steven E. Artandi from Stanford School of Medicine, along with collaborators from NIH's National Cancer Institute (NCI) and the University of Georgia, set out to identify the unknown components. In work funded by NCI, NIH's National Institute of General Medical Sciences (NIGMS) and the Leukemia and Lymphoma Society, they used a highly sensitive protein detection system called nano-liquid chromatography-tandem mass spectrometry to find proteins that bind to known components of telomerase.

As they reported in Science on January 30, 2009, the approach led to the discovery of TCAB1 (telomerase Cajal body protein 1). TCAB1 is primarily associated with Cajal bodies—structures in the nucleus known to be important for telomere synthesis.

The scientists found that TCAB1 depletion didn't affect telomerase activity in the lab. They next used a technique called RNA interference to silence TCAB1 gene expression in cells. With TCAB1 silenced, telomerase no longer localized to Cajal bodies, preventing telomere elongation. Thus, TCAB1 plays a role in directing the telomerase complex through Cajal bodies to telomeres at the ends of newly divided chromosomes.

These results suggest a potential new cancer target. Selectively blocking TCAB1 in cancer cells could inhibit telomerase activity and keep cancer cells from dividing indefinitely.

“This is the first major new protein component of telomerase that has been identified in 10 years,” Artandi said. “And it's likely to be a valuable target for anticancer therapies.”

—by Nancy Van Prooyen

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