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Targeting telomerase to slow cancer growth

Graduate student Matthew Schaich forges ahead with research efforts, career aspirations, despite added challenges of pandemic.  
Graduate student Matthew Schaich

July 16, 2020

Matthew “Matt” Schaich, is set to receive his Doctor of Philosophy degree in biochemistry and molecular biology at the end of the summer. He has spent the last four years working in the lab of Bret Freudenthal, PhD, associate professor, who is a member of The University of Kansas Cancer Center’s Cancer Biology research program. Matt was Dr. Freudenthal’s first rotation student and joined the lab just a few months after its launch in 2016.

The overarching goal of Dr. Freudenthal’s lab is to fill the knowledge gap between DNA damage and diseases, including cancers. This research focus, as well as the strong sense of community and team spirit between its members, is what drew Matt to Dr. Freuenthal’s lab. Since joining, Matt has worked on several studies related to genome stability, as well as learned how to analyze proteins using x-ray crystallography, which uses an x-ray diffractometer to “shoot” tiny crystals, similar to grains of salt, with x-rays, allowing researchers to determine three-dimensional structures of proteins in complex with DNA.

“I still remember the first time I solved a crystal structure in Dr. Freudenthal’s lab. After a day of intricate pipetting, I managed to pick up a tiny crystal under a microscope and placed it on the x-ray crystallography machine,” Matt recalled. “After blasting the crystal for about 24 hours with high-powered x-rays and collecting data made up of how the x-rays ‘bounce’ off of the crystal, I had solved the complete 3D structure.”

Matt was especially struck by the sight of DNA, which he’d only read about in textbooks.

“After many years of reading about how DNA looks and seeing artistic interpretations in movies and pop culture, I could see the classic double-helix displayed on my monitor. I remember the picture was so crystal clear and detailed I could even zoom in and read the genetic code without having to submit the DNA for sequencing.”

Telomeres & telomerase

Despite the challenges of conducting research in a pandemic, Dr. Freudenthal and his team have forged ahead with their work. One of their studies was recently published in eLife, and it focuses on a tiny – yet very important – part of the human chromosome, called a telomere. Like the plastic tip at the end of a shoelace, telomeres sheath and protect each end of a chromosome. Telomeres contain a short DNA sequence that repeats over and over again. As we age and our bodies are exposed to oxidative stress, our cells divide, and the telomeres shorten.

“Over time, these telomeres become very short, and if cells kept on dividing, they would start to chew away their DNA, leading to the catastrophic loss of genes,” explained Matt. “To keep this from happening, your cells undergo senescence, which means they stop dividing. Senescent cells are associated with age.”

Enter telomerase, an enzyme that plays the important role of re-extending telomeres by adding a repeating sequence of nucleotides, the basic building block of nucleic acids. Telomerase is found in high concentrations in stem cells, as well as cancer cells. Cancer cells are dependent on cell division, which fuels tumor growth.

“Without telomerase to extend telomeres, the cancer cells would just eat their DNA. If you could target telomerase activity, you could theoretically stop cancers from growing,” Matt said.

To see is to understand

Using x-ray crystallography, the team set out to document telomeres in the act of being extended by telomerase. After thousands of attempts to capture the act at the molecular level, an extremely small scale, they got it.

 

 Telomerase

The yellow curls in the image are the telomerase enzyme and the white lines represent the telomere strand. The purple strand in the helix represents the RNA template of telomerase, which contains the genetic code needed to lengthen telomeres.

A key observation from this study provides insight into how telomerase selects the right nucleotides, (deoxyribonucleotides) from the wrong nucleotides (ribonucleotides) to maintain telomere integrity. Interestingly, the cellular environment is rich with ribonucleotides, and Dr. Freudenthal and his team were the first to identify the mechanism that keeps ribonucleotides out of telomeres.

Dr. Freudenthal added that the findings from this study are particularly exciting because the team demonstrated how telomerase works, how it selects the right nucleotide, as well as identified a residue that prevents ribonucleotides from accumulating in telomeres, which Matt determined through advanced enzymology.

Growing future scientists

As a National Cancer Institute (NCI)-designated institution, cancer center members are committed to training and educating the next generation of scientists, clinicians and healthcare professionals. Our leaders and programs put students on the leading-edge of science in a variety of fields.

Dr. Freudenthal has mentored multiple graduate students, including Matt, over the years.

“Mentoring the next generation of scientists is the best part of my job,” Dr. Freudenthal said. “Interacting with energetic, talented and passionate trainees makes every new experimental result a true joy. I still remember the day Matt solved and shared his structure of telomerase with me on Christmas Eve. The shared excitement, even via email, will be a moment I associate with his work on telomerase.”

Dr. Freudenthal added that to understand cancer, scientists who work in basic, translational and clinical research are necessary.

“This combination of disciplines is the only way we can overcome the challenges associated with beating cancer. Our laboratory works to understand the basic molecular details of cancer, and being part of the cancer center provides an amazing environment to train the next generation of scientists,” Dr. Freudenthal said.

Matt, who received the Karen B. and Kelly D. Gregg Graduate Student award in 2019, is expected to graduate in August 2020. He has encountered some interesting challenges navigating his next career move, which involves securing a postdoctoral fellowship. Due to the COVID-19 crisis, the usual in-person visits and interviews have been replaced with video conference calls.

“The work we did with telomerase helped us better understand how telomerase works, but is only one step forward of many needed to bring telomerase-targeting cancer therapeutics to the clinic,” Matt said. “As I look to the next phase of my career, I hope to continue to be a part of the push towards bringing new therapeutics to the clinic by learning about them from a mechanistic stage to better inform translational outcomes. The University of Kansas Cancer Center has had an enormous impact on my career growth, not only from a training standpoint but also in terms of helping me build my network. I have had the opportunity to interact with some of the top researchers who’ve visited the University of Kansas Medical Center to give seminars and presentations. I now have several phenomenal opportunities I am considering around the country for the next stage.”

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