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An enzyme involved in cancer and aging gets a close-up

Understanding what telomerase looks like could guide therapies for cancer, other illnesses

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10:00am, May 4, 2018
telomerase

HANDY ADD  Telomerase (bottom structure), a complex of proteins and RNA, adds DNA to telomeres (green caps), the ends of chromosomes (blue X’s). The telomeres shorten when cells divide.

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Like a genetic handyman, an elusive enzyme deep inside certain cells repairs the tips of chromosomes, which fray as cells divide. It’s prized by rapidly dividing cells – like stem cells and tumor cells – and by scientists on the hunt for cancer and other disease therapies.

Now researchers have the best picture yet of this enzyme, called telomerase. Using cryo-electron microscopy, structural biologist Kelly Nguyen and her colleagues describe the structure of telomerase at a resolution of 0.7 to 0.8 nanometers, three times better than the last attempt.

This close-up reveals how the enzyme’s proteins and RNA are put together, potentially offering insight into ways to fight cancer and understand genetic diseases caused by faulty versions of the enzyme, the researchers report online April 25 in Nature.

The discovery of telomerase in 1984 earned a team of biologists the 2009 Nobel Prize in medicine (SN: 10/24/09, p.14). Since then, scientists have pieced together connections between the enzyme’s activity and cancer, aging and inherited disorders. But the development of therapies has suffered from the lack of a detailed snapshot of the enzyme.

One difficulty is that there is very little of the enzyme in the body. Nguyen, of the University of California, Berkeley, says that she and one of her coauthors “grew thousands and thousands of plates of human cells” to collect enough telomerase to work with.

The team’s images reveal a two-lobed structure, held together by RNA, Nguyen says. One lobe contains proteins that put all of the pieces of telomerase together and make sure the enzyme gets to the right place in the cell.

The other lobe contains the enzyme that adds DNA to the ends of chromosomes, called telomeres, which are made of repeated DNA stretches. Telomeres lose DNA with each cell division, and telomerase lengthens them again, to protect the chromosomes’ genetic information. Along with providing structural support, the RNA guides telomerase as it adds DNA to telomeres.

The work provides an “unprecedented view” of how the parts of telomerase are organized, biophysicist Michael Stone of the University of California, Santa Cruz, wrote in a commentary accompanying the study.

“One can generally think of any required step in that assembly process as a potential therapeutic target,” Stone says in an interview. But to assist in developing treatments, he says, researchers will need to capture telomerase at a resolution of 0.3 to 0.4 nanometers, which will reveal how the enzyme’s atoms interact. “The more that you know how the machine is put together, the more you can imagine ways of putting a jam into the machine.”

Citations

T.H.D. Nguyen et al. Cryo-EM structure of substrate-bound human telomerase holoenzyme. Nature. Published online April 25, 2018. doi:10.1038/s41586-018-0062-x

Michael D. Stone. Detailed view of human telomerase enzyme invites rethink of its structure. Nature. Published online April 25, 2018. doi:10.1038/d41586-018-04756-3

Further Reading

C. Gramling and L. Hamers. Chemistry Nobel Prize goes to 3-D snapshots of life’s atomic details. Science News. Vol. 192, October 28, 2017, p. 6.

T.H. Saey. Nobel in medicine honors discoveries of telomeres and telomerase. Science News. Vol. 176, October 24, 2009, p. 14.

P. Barry. Reading the repeats: cells transcribe telomere DNA. Science News. Vol. 173, January 5, 2008, p. 6.

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