May 04, 2014

ASU, Chinese scientists unlock secrets of the fountain of youth

Posted: May 04, 2014
Julian Chen and graduate student Dustin Rand conduct research at ASU
Julian Chen and his graduate student Dustin Rand in their ASU lab continuing research on the protein-RNA interaction in the vertebrate telomerase complex. Doctoral students Christopher Bley and Andrew Brown, also involved with the work, have graduated.
Photo by: Joshua Podlevsky
diagram of the enzyme telomerase complex
The ends of chromosomes are capped by telomeres (black), protective structures composed of DNA (black) and proteins (grey). Telomeres are maintained by telomerase, a highly complicated enzyme, composed of numerous proteins (pink and red) and an intrinsic RNA component (light green and green). The atomic level structure of the Telomerase RNA Binding Domain (TRBD, red) binding the CR4/5 RNA (green) component was recently determined by X-ray crystallography.
Photo by: Joshua Podlevsky
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Arizona State University scientists, together with collaborators from the Chinese Academy of Sciences in Shanghai, have published a first of its kind atomic level look at the enzyme telomerase that may unlock the secrets to the fountain of youth in the journal Nature Structural and Molecular Biology.

Telomeres and the enzyme telomerase have been in the medical news a lot recently, due to their connection with aging and cancer. Telomeres are found at the ends of our chromosomes and are stretches of DNA which protect our genetic data, make it possible for cells to divide and hold some secrets as to how we age – and also how we get cancer.

An analogy can be drawn between telomeres at the end of chromosomes and the plastic tips on shoelaces: the telomeres keep chromosome ends from fraying and sticking to each other, which would destroy or scramble our genetic information.

Each time one of our cells divides, its telomeres get shorter. When they get too short, the cell can no longer divide, and it becomes inactive or dies. This shortening process is associated with aging, cancer and a higher risk of death. The initial telomere lengths may differ between individuals. Clearly, size matters.

“Telomerase is crucial for telomere maintenance and genome integrity,” explains Julian Chen, professor of chemistry and biochemistry at ASU and one of the project’s senior authors. “Mutations that disrupt telomerase function have been linked to numerous human diseases that arise from telomere shortening and genome instability.”

Chen continues that, “Despite the strong medical applications, the mechanism for telomerase holoenzyme (the most important unit of the telomerase complex) assembly remains poorly understood. We are particularly excited about this research because it provides, for the first time, an atomic level description of the protein-RNA interaction in the vertebrate telomerase complex.”

The other senior author on the project is professor Ming Lei, who has recently relocated from the University of Michigan to Shanghai, China, to lead a new National Center for Protein Science (affiliated with the Chinese Academy of Sciences).

At its core, telomerase is composed of two principle components: 1) a catalytic protein which synthesizes DNA from a template located within and 2) an intrinsic RNA component.  Chen's laboratory has recently developed a means to highly purify an independently functional fragment of the telomerase protein.  This functional telomerase protein fragment is aptly termed, Telomerase RNA Binding Domain (TRBD) for its RNA binding function.  Additionally, Chen’s researchers employed their purified protein to determine the specific region within TRBD responsible for binding a fragment of the telomerase RNA component, termed CR4/5.

The collaboration with Lei's group enabled the two laboratories to generate highly pure TRBD protein and successfully assemble this with the CR4/5 RNA for X-ray crystallography.  X-ray crystallography involves bombarding the protein-RNA complex with high energy X-rays, which then scatter.  By interpreting the scatter pattern, Lei’s laboratory was able to determine the structure of the protein-RNA crystal, providing important insights into the binding of the RNA by the protein.  

The mysteries of telomerase protein and RNA assembly are beginning to be exposed, with the exhaustive work of researchers within the telomerase field.  The findings of professors Chen, Lei, and many others are improving our understanding of this fundamentally essential enzyme, slowly divulging its secrets which will be applied towards the development of therapeutics to enhance human health. 

The Department of Chemistry and Biochemistry in ASU's College of Liberal Arts and Sciences ranks 6th worldwide for research impact (gauged by the average cites per paper across the department for the decade ending in the 2011 International Year of Chemistry), and in the top eight nationally for research publications in the journals Science and Nature. The department’s strong record in interdisciplinary research is also evidenced by its 31st national ranking by the National Science Foundation in total and federally financed higher education research and development expenditures in chemistry.

This work was supported by grants from the US National Institutes of Health (RO1GM094450 to J.J.-L.C.), Ministry of Science and Technology of China (2013CB910400 to M.L.) and the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB08010201 to M.L.).

Jenny Green, jenny.green@asu.edu
480-965-1430
Department of Chemistry and Biochemistry