A $10.6 million grant from the National Institutes of Health (NIH) will allow the University of Arkansas for Medical Sciences (UAMS) to greatly expand its proteomics resource. This grant will establish the IDeA National Resource for Quantitative Proteomics as the first NIH National Resource in Arkansas, which will serve biomedical researchers across the nation.

Proteomics is the large-scale study of proteins that can lead to the development of new therapies and screening approaches for many diseases, including cancer.

The five-year grant was awarded to Alan Tackett, Ph.D., professor in the Department of Biochemistry and Molecular Biology and associate director for basic science at the UAMS Winthrop P. Rockefeller Cancer Institute. Tackett serves as an administrative director of this new national resource.

Other key contributors at UAMS are Rick Edmondson, Ph.D.; Samuel Mackintosh, Ph.D.; and Stephanie Byrum, Ph.D.; as well as Michael Kinter, Ph.D., at the Oklahoma Medical Research Foundation who serves as a co-administrative director.

The national resource was initially created through the Arkansas INBRE (IDeA Network of Biomedical Research Excellence) — an NIH program that promotes biomedical research for undergraduate students and faculty. Lawrence Cornett, Ph.D., professor in the UAMS College of Medicine Department of Physiology and Biophysics, serves as principal investigator and director of Arkansas INBRE.

“With this new funding, we will transition our proteomics resource to an NIH National Resource and expand our ability to provide highly advanced research support to scientists in underfunded areas throughout the United States,” said Tackett, who holds the Scharlau Family Endowed Chair for Cancer Research at UAMS.

Certain regions of the United States, designated as the IDeA Network, have historically received low levels of research funding from NIH. Scientists in these regions face challenges for accessing state-of-the-art proteomics resources.

The IDeA National Resource for Quantitative Proteomics at UAMS was established to address these gaps in services.

“Due to a lack of federal funding, it is often difficult for scientists in the IDeA Network to access the advanced instruments and trained personnel needed to analyze and interpret their research data. With this new funding, we will now be able to serve a diverse group of IDeA investigators for their research, which ranges from studies on model organisms to diseases such as cancer,” said Tackett, professor of biochemistry and molecular biology in the UAMS College of Medicine.

The expanded national resource will support researchers by providing highly advanced data analysis, outreach opportunities and education to scientists across the nation.

“Our goal is to increase the ability for scientists in the 23 IDeA states and Puerto Rico, as well as other NIH-supported investigators across the nation, to perform innovative research by providing unmatched access to advanced quantitative proteomics platforms and staff skilled in interpreting and analyzing complex biological data,” Tackett said.

The educational opportunities offered by the national resource include workshops that are designed to help faculty and student researchers across the nation better utilize proteomics in their research.

This federal grant will bolster the Cancer Institute’s ongoing efforts to receive National Cancer Institute Designation. To achieve designation, cancer centers undergo a highly competitive assessment process that demonstrates an outstanding depth and breadth of research in three areas: basic laboratory, patient/clinical and population-based. The designation brings with it many benefits, including expanded access to federal funding for researchers and improved access to clinical trials for patients.

Dr. Alan Tackett, Professor of Biochemistry and Molecular Biology, has been invited to serve as a standing member of the NIH Mechanisms of Cancer Therapeutics-1 (MCT1) Study Section, one of the major review boards for evaluation of cancer research by the Center for Scientific Review. The four-year appointment recognizes Dr. Tackett, who also serves as the Scharlau Family Endowed Chair in Cancer Research at UAMS, as a leader in this field. Congratulations to Dr. Tackett.

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Congratulations to Dr. Grover Miller, Professor of Biochemistry and Molecular Biology, on his appointment to the Xenobiotic and Nutrient Disposition and Action (XNDA) Study Section in the National Institutes of Health’s Center for Scientific Review. Dr. Miller will serve a four-year term on the panel, whose members are selected for their excellence and achievement in their scientific discipline. At UAMS, Dr. Miller and his team develop and apply new and powerful strategies to better assess drug liabilities that cause significant adverse drug events including cardio- and hepato-toxicity.

Congratulations to postdoctoral fellow Maroof Zafar and his co-authors, Lindsey Hazeslip, Zain Chauhan, and Alicia Byrd.  Cover art by Lindsey Hazeslip for their recent article on regulation of expression by non-canonical G-quadruplexes was selected for the cover of the July 2020 issue of Biochemistry.

LITTLE ROCK — A research team led by cancer researcher Justin Leung, Ph.D., at the University of Arkansas for Medical Sciences (UAMS) has uncovered the role of the protein RNF168 in DNA damage repair and shown how mutations of the protein affect people with a rare genetic condition.

The study titled “Histone H2A variants alpha1-extension helix directs RNF168-mediated ubiquitination” was published in the May 18 issue of the open-access journal Nature Communications.

“Every day our cells are subjected to environmental sources of DNA damage, such as ultraviolet radiation and toxic chemical exposure. If left unrepaired, these damages can accumulate, leaving mutations in our DNA and ultimately cause cells to become cancerous,” said Leung, assistant professor in the UAMS College of Medicine Department of Radiation Oncology.

In most cases, this damage is detected and repaired by a tightly regulated method involving many proteins. To develop better cancer therapies, researchers such as Leung strive to understand the regulation of DNA damage and repair by sensitizing cells to radiation therapy and chemotherapy drugs that target DNA.

“Our lab studies the repair of double stranded breaks, where both strands of DNA are broken apart completely. When a double strand break occurs, a cascade of protein activity is set off to try to resolve the damage,” Leung said.

Mutations in one of these proteins, RNF168, have been found in patients with RIDDLE syndrome, a rare genetic disorder that increases a person’s predisposition to blood cancer and is characterized by several attributes:

• Susceptibility to DNA damaging agents
• Immunodeficiency, or failure of the immune system to protect the body from infection
• Developmental abnormalities
• Learning disabilities

RNF168 adds a small signaling molecule called ubiquitin onto a subunit of chromatin, where we store our genetic information. The ubiquitin signal brings repair proteins to DNA double strand breaks. However, exactly how RNF168 recognizes the specific target remains unclear.

Using molecular and structural analysis methods, Leung’s team uncovered crucial components of RNF168 and chromatin required for the implementation of repair pathways in response to DNA damage. Their findings suggest that a recognition between RNF168 and chromatin is required to activate the downstream DNA repair processes.

“RNF168 is a central DNA damage response protein. Understanding the precise mechanisms by which it activates its targets is essential for understanding how the DNA damage response goes awry. Our results help demystify the role of RNF168 in proper DNA damage repair and understand the implications of RNF168 mutations such as those seen in RIDDLE syndrome,” Leung said.

UAMS authors for this study included Jessica Kelliher, B.S., research assistant, and Kirk West, Ph.D., postdoctoral fellow.