News

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.

By Susan Van Dusen

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.

Alan Diekman, Ph.D., was honored as the 2020 Master Teacher in recognition of his work with first-year medical students. When College of Medicine students are asked about their best teachers, Diekman’s name comes up often. As director of the Molecules to Cells course, Diekman teaches first-year students and works with other faculty to ensure the students gain a firm grasp of biochemistry, cell biology and genetics – including complex concepts that many medical students nationwide struggle to grasp.

“Most importantly, he has convinced students that understanding molecular and cellular mechanisms is an important part of their medical training,” Department of Physiology and Biophysics Chair Michael Jennings, Ph.D., wrote in a letter of support for Diekman, who has served on the faculty since 2002.

“The word ‘outstanding’ may underestimate the quality of Dr. Diekman’s teaching effort, ability and outcomes,” Biochemistry and Molecular Biology Chair Kevin Raney, Ph.D., wrote in his nomination letter. “He is a superb communicator who treats students respectfully, while maintaining high expectations. Dr. Diekman also sets high standards for his colleagues, thereby improving the quality of teaching of those around him.”

James Graham, M.D., executive associate dean for academic affairs in the college, also wrote in support, noting strong performance by UAMS students in areas of the notoriously difficult United States Medical Licensing Exam Step 1 that are covered in Diekman’s course, as well as improved overall performance on the exam in recent years. Diekman has been instrumental in major curriculum revisions that change how first- and second-year medical students prepare for their clinically focused training.

“I am very honored by this recognition from my colleagues, and I thank them for their past support,” said Diekman. “The privilege of educating our medical students in the complex disciplines of biochemistry, cell biology and genetics is both challenging and fulfilling. My goal is to provide our students with a firm foundation in these disciplines, not just for their sake, but also for that of their future patients.”

Genome Maintenance by DNA Helicase B.

Selective Survival of Sim1/MC4R Neurons in Diet-Induced Obesity.

Dual mechanisms suppress meloxicam bioactivation relative to sudoxicam.

 

Advances in the study of drug metabolism – symposium report of the 12th Meeting of the International Society for the Study of Xenobiotics (ISSX).

The UAMS Graduate School held a virtual hooding ceremony which you can read more about here. The Biochemistry and Molecular Biology Department graduated three students last year. Tresor Mukiza, Ph.D. is now a postdoctoral fellow in Joseph Opferman’s lab at St. Jude Children’s Research Hospital. Tresor’s mentor at UAMS was Wayne Wahls. Eugene Nyamugenda, Ph.D. is now a postdoctoral fellow in Ravi Allada’s lab at Northwestern University in the Department of Neurobiology. Eugene’s mentor at UAMS was Giulia Baldini. Bradley Shields, M.D., Ph.D. is beginning a residence in dermatology at Intermountain Medical Center and the University of Pittsburgh Medical Center. Bradley’s mentor at UAMS was Alan Tackett.

Alan Tackett, a professor in the Department of Biochemistry and Molecular Biology, was featured in a story on KARK this morning about clinical trials at UAMS.

Assistant Professor
Department of Biochemistry and Molecular Biology
UAMS College of Medicine
Co-Director, Winthrop P. Rockefeller Cancer Institute Proteomics Shared Resource and UAMS Proteomics Core Facility

Research Interest Statement

My research interests are focused on proteomics and mass spectrometry. As co-director of the Proteomics Shared Resource and UAMS Proteomics Core Facility, I am involved in a wide variety of basic and translational research projects and collaborations at any given time. The core facility maintains and operates five state-of-the-art mass spectrometers, two of which I secured for the facility with NIH shared instrument grants. The core lab offers cutting-edge, affordable proteomics analysis to all UAMS investigators and Cancer Institute members. Our facility is nationally recognized with users in 35 states and Puerto Rico, and our research is routinely published in high-impact, peer-reviewed journals. We work closely with other researchers to help them design proteomics experiments, apply for grants and publish papers. We offer complete sample processing services so that our collaborators can submit samples they can easily prepare in their own labs. We also work closely with the UAMS Bioinformatics Core to prepare data for our collaborators in publication-ready formats.

Dr. Mackintosh’s Cancer–related Grants

NIH/NIGMS: 1S10OD026736

Samuel Mackintosh: Project PI

Title “Q Exactive HF-X Hybrid Quadrupole Orbitrap Mass Spectrometer”

08/01/2019 to 07/31/2020

$763,961*

*project direct cost

As part of Dr. Mackintosh’s role as co-director of the Winthrop P. Rockefeller Cancer Institute Proteomics Shared Resource and UAMS Proteomics Core Facility, he also serves as Co-I on the ACRI/UAMS COBRE grant (Center for Translational Pediatric Research, PI: Alan Tackett PhD., NIH award P20GM121293) and the UAMS INBRE grant (Partnerships for Biomedical Research in Arkansas, PI: Larry Cornett PhD., NIH award P20GM103429).

Dr. Mackintosh’s UAMS Collaborators

• College of Medicine
  • Department of Internal Medicine
    • John Arthur, M.D., Ph.D.
    • Jawahar Mehta, M.D., Ph.D.
  • Department of Geriatrics
    • Srinivas Ayyadevara, Ph.D.
    • Richard Dennis, Ph.D.
    • Robert Reis, Ph.D.
  • Department of Biochemistry and Molecular Biology
    • Giulia Baldini, Ph.D.
    • Marie Burdine, Ph.D.
    • Alicia Byrd, Ph.D.
    • Stephanie Byrum, Ph.D.
    • Tim Chambers, Ph.D.
    • Rick Edmondson, Ph.D.
    • Robert Eoff, Ph.D.
    • Samantha Kendrick, Ph.D.
    • Grover Miller, Ph.D.
    • Kevin Raney, Ph.D.
    • Aaron Storey, Ph.D.
    • Alan Tackett, Ph.D.
    • Wayne Wahls, Ph.D.
    • Boris Zybaylov, Ph.D.
  • Department of Neurobiology and Developmental Sciences
    • Edgar Garcia-Rill, Ph.D.
    • Angus MacNicol, Ph.D.
  • Department of Biochemistry and Molecular Biology
    • Renny Lan, Ph.D.
  • Department of Pathology
    • Mayumi Nakagawa, M.D., Ph.D.
    • Steven Post, Ph.D.
  • Department of Physiology and Biophysics
    • Roy Morello, Ph.D.
  • Department of Microbiology and Immunology
    • Mark Smeltzer, Ph.D.
• College of Pharmacy
  • Department of Pharmaceutical Sciences
    • Martin Hauer-Jensen, M.D., Ph.D.
• College of Public Health
  • Department of Environmental and Occupational Health
    • Mitch McGill, Ph.D.
    • Gunnar Boysen, Ph.D.

Dr. Mackintosh’s External Collaborators

• Randy Haun, Ph.D., Arkana Laboratories
• Jeffrey Lewis, Ph.D., UA-Fayetteville
• Arthur Salomon, Ph.D., Brown University
• Sean Taverna, Ph.D., Johns Hopkins University
• Greg Wang, Ph.D., University of North Carolina
• Michael Wang, M.D., MD Anderson Cancer Center
• Michael Washburn, Ph.D., Stowers Institute for Medical Research
• Andrew Xiao, Ph.D., Yale University
• Qin Yan, Ph.D., Yale University
• Daohong Zhou, M.D., University of Florida

Opportunities for Collaboration

The resources of the Proteomics Core are available to anyone at UAMS, and there are pilot funding opportunities available for Cancer Institute members.

Each year the editors of GSA journals select for distinction some of the year’s top scientific publications.  Congratulations to Aaron Storey, Hsin-Ping Wang, Reine Protacio, Mari Davidson and Wayne Wahls.  Their research article on Targeted Forward Genetics was featured in the GSA’s annual Spotlight:  A showcase of research and scholarship in selected articles from 2019. The work was supported by a research project grant (GM081766) from the National Institute of General Medical Sciences to Wayne Wahls.

GENETICS SOCIETY OF AMERICA EDITORS’ NOTE  Storey et al. describe a powerful methodology for precisely-targeted, saturating mutational analyses of discrete chromosomal elements in situ.  In this method, more than 100,000 independent allele replacements, distributed over long regions of the target locus, can be generated simultaneously in each experiment.  The approach efficiently generates and identifies functionally-null and hypomorphic mutations throughout the targeted region.  This process of population-scale, targeted forward genetics over large distances allows scientists to rapidly dissect the structure and function of specific chromosomal elements and their encoded factors under native, biologically relevant conditions.