The biochemistry department participated in the 18th Annual Village Walk for Cancer Research in Hot Springs Village. The walk is a fundraiser for cancer research at WPRCI. Funds from last years walk are currently funding a project addressing drug resistance in lymphoma in Samantha Kendrick‘s lab. Also walking were Stephanie Byrum, Alicia Byrd, and Tung-chin Chiang.
The Biochemistry and Molecular Biology welcomed new GPIBS students to UAMS with a picnic at Allsopp Park. Thanks to students Katie Bronson and Allie Davis for helping with the organization and set up.
Katie Bronson and Allie Davis
Allie Davis, a graduate student in Dr. Paul Miller’s lab, and Binyam Belachew, a graduate student in Dr. Kevin Raney’s lab received their white coats at the UAMS Graduate School’s annual Research Induction Ceremony celebrating Ph.D. candidates who have successfully passed their qualifying exam in the past year. Congratulations Allie and Binyam!
Allie Davis, a graduate student in Dr. Grover Paul Miller’s lab has recently been elected to two different groups.
Allie was elected to serve on the International Society for the Study of Xenobiotics (ISSX) New Investigator Group. This group comprises promising new investigators (predoctoral, postdoctoral, and new to their careers) that recruit and retain new ISSX members and promote interaction and collaborations between new members and more experienced members to ensure a lively and diverse group for many years to come. Currently, the new investigator group is writing up a conference proceedings paper that covers the ISSX international meeting from this past July.
Allie was also selected to serve on the Drug Metabolism Reviews (DMR) editorial board. Being a predoctoral student, access to many editor friends and colleagues she’s met at conferences and events will help her to learn the editorial process. Allie was selected for this group because she is a promising new investigator who has shown that she is willing and able to communicate and collaborate with scientists across many branches with varying degrees of experience.
Congratulations Allie!
Maroof Zafar, a postdoctoral fellow in Alicia Byrd’s lab, was the featured visitor of the week at Cold Spring Harbor Labs when he attended the CSHL Eukaryotic DNA Replication & Genome Maintenance Meeting. Check out the article about him.
Megan Reed, a graduate student in Robert Eoff’s lab presented a poster entitled “DNA polymerase kappa modulates glioma cell plasticity in response to DNA damage” at the Cold Spring Harbor Labs Eukaryotic DNA Replication & Genome Maintenance Meeting.
Maroof Zafar, a postdoctoral fellow in Alicia Byrd’s lab presented a poster entitled “Human DNA helicase B protects stalled forks from degradation after replication stress” at the Cold Spring Harbor Labs Eukaryotic DNA Replication & Genome Maintenance Meeting.
Davis LE, Shalin SC, Tackett AJ.
Cancer Biol Ther.
PHF19 promotes multiple myeloma tumorigenicity through PRC2 activation.
Ren Z, Ahn JH, Liu H, Tsai YH, Bhanu NV, Koss B, Allison DF, Ma A, Storey AJ, Wang P, Mackintosh SG, Edmondson RD, Groen RWJ, Martens AC, Garcia BA, Tackett AJ, Jin J, Cai L, Zheng D, Wang GG.
Blood.
Glazko G, Zybailov B, Emmert-Streib F, Baranova A, Rahmatallah Y.
PLoS One
Researcher Robert Eoff, Ph.D., has received a $1.2 million grant from the National Science Foundation to continue his work at the University of Arkansas for Medical Sciences (UAMS) on DNA damage, cell replication and its implications for diseases like dementia, ALS and cancer.
Eoff is an associate professor in the Department of Biochemistry and Molecular Biology in the UAMS College of Medicine and a member of UAMS’ Winthrop P. Rockefeller Cancer Institute. Julie Gunderson, Ph.D., assistant professor of physics at Hendrix College in Conway, is collaborating with Eoff on the project. The four-year grant will also support graduate student training at UAMS and undergraduate trainees at Hendrix.
Eoff’s research team studies what happens when DNA damage is not repaired in a timely manner and ends up blocking the mechanics behind how copies of new cells are made. Specifically, he studies the effect of large amounts of guanine in DNA sequences, which can form unusual structures called G-quadruplexes (G4).
“Imagine trying to copy a document containing over six billion letters in the span of a few hours,” Eoff said. “Now imagine finding that the text contains many words like ‘Mississippi,’ ‘Czechoslovakia,’ ‘Oberschleissheim’ and ‘Solgohachia.’ Even though you’re on a tight schedule, you might have to slow down a bit when you come to those tricky words.
“As it turns out, this is probably a good analogy for what happens when enzymes involved in DNA replication encounter certain sequences that contain an abundance of guanine bases,” Eoff said.
Errors in these G4 sequences can lead to changes in the genome that are associated with human disease. For example, neurological diseases such as frontotemporal dementia, amyotrophic lateral sclerosis (ALS), and the intellectual disability fragile X syndrome have all been linked to dysfunctional G4 maintenance.
There is also a substantive and growing body of literature linking G4 to the biology of cancer and cancer therapies. Many cancer-related genes are controlled by G4 motifs, and chromosomes in tumor specimens tend to be broken more frequently near G4 sites than other DNA sequences.
However, scientists do not fully understand how these errors occur.
For this specific grant, Eoff will study the role of a special enzyme called Rev1 in copying G4 sequences. Rev1 is a DNA polymerase — an enzyme that catalyzes synthesis of new strands of DNA.
“Successful completion of this research will give us a better understanding of how G4 replication errors occur and how they might have come about in the first place,” Eoff said. “Hopefully, this will give us new insight into replication barriers, which cause a wide range of issues in humans and other species, as a first step toward putting this greater understanding to use in the form of new treatments and therapies.”
Assistant Professor
Department of Biochemistry and Molecular Biology
UAMS College of Medicine
DNA damage occurs tens of thousands of times per day in human cells from both endogenous and environmental sources. In order to preserve the genetic material, cells have evolved multiple mechanisms to detect and repair DNA damage. Mutations in genes encoding proteins involved in the DNA damage response result in a variety of DNA repair syndromes, which have increased risks of cancers, often in childhood. However, inaccurate DNA repair can also cause genomic instability such as chromosomal rearrangements and expansion of repetitive sequences, which can lead to the development of cancer.
My research focuses on the enzymes that regulate the DNA damage response, in particular, a family of enzymes called helicases that remove secondary structures from DNA. These proteins have critical roles in DNA repair and loss of activity results in genomic instability and predisposition to many types of cancer. The molecular mechanisms of these proteins, both individually and as components of multi-protein complexes, are of interest, as are the effects of posttranslational modifications on their activity. Increased understanding of the regulation of these DNA repair processes that are critical for maintaining genomic integrity could ultimately lead to the design of better cancer therapies.
Winthrop P. Rockefeller Cancer Institute
Seeds of Science Pilot Award
Regulation of the DNA Damage Response in Breast Cancer
2/1/19 – 1/31/20
$15,000*
NIGMS – 3 R35 GM122601-03S1
Functions and Mechanisms of Helicases and G-Quadruplex Nucleic Acids
5/01/2017-4/30/2022
Role: Co-I (Kevin Raney, PI)
$129,583*
*cancer-related annual direct costs
Stephanie Byrum, Ph.D. (Department of Biochemistry and Molecular Biology)
Robert Eoff, Ph.D. (Department of Biochemistry and Molecular Biology)
Kevin Raney, Ph.D. (Department of Biochemistry and Molecular Biology)
Samantha Kendrick, Ph.D. (Department of Biochemistry and Molecular Biology)
Justin Leung, Ph.D. (Department of Radiation Oncology)
Nirmala Parajuli, DVM, Ph.D. (Department of Pharmacology and Toxicology)
Mark Dillingham, Ph.D. (University of Bristol)
I am just beginning my independent research program at UAMS and welcome new collaborations. My primary area of interest is the DNA damage response, but anything related to genome maintenance interests me. My lab has expertise in enzymology, protein-DNA interactions, and G-quadruplex DNA, and we are particularly interested in breast cancer.
I have visited 48 of the 52 Arkansas State Parks with my family on a geocaching adventure. Petit Jean is my favorite so far, but stay tuned; we have four parks left to see.
Gao J, Byrd AK, Zybailov BL, Marecki JC, Guderyon MJ, Edwards AD, Chib S, West KL, Waldrip ZJ, Mackintosh SG, Gao Z, Putnam AA, Jankowsky E, Raney KD. (2019) DEAD-box RNA helicases Dbp2, Ded1 and Mss116 bind to G-quadruplex nucleic acids and destabilize G-quadruplex RNA. Chem Commun (Camb). 55, 4467-4470.
Marecki, JC, Aarattuthodiyil S, Byrd AK, Penthala NR, Crooks PA, Raney KD (2019) N-Naphthoyl-substituted indole thio-barbituric acid analogs inhibit the helicase activity of the hepatitis C virus NS3. Bioorg Med Chem Lett. 29, 430-434.
Byrd AK, Bell, MR, Raney KD (2018) Pif1 helicase unfolding of G-quadruplex DNA is highly dependent on sequence and reaction conditions. J Biol Chem. 293, 17792-17802.
Byrd AK and Raney KD (2017) Structure and function of Pif1 helicase. Biochem Soc Trans. 15, 1159-1171.
Griffin WC, Gao J, Byrd AK, Chib S, Raney KD. (2017) A biochemical and biophysical model of G-quadruplex DNA recognition by positive coactivator of transcription 4. J Biol Chem. 292, 9567-9582.
Byrd AK, Zybailov BL, Maddukuri L, Gao J, Marecki JC, Jaiswal M, Bell MR, Griffin WC, Reed MR, Chib S, Mackintosh SG, MacNicol AM, Baldini G, Eoff RL, Raney KD. (2016) Evidence that G-quadruplex DNA Accumulates in the Cytoplasm and Participates in Stress Granule Assembly in Response to Oxidative Stress. J Biol Chem. 291, 18041-57.
A grant of almost $764,000 from the National Institutes of Health (NIH) will allow the University of Arkansas for Medical Sciences (UAMS) to purchase biomedical research equipment with new capabilities unavailable elsewhere in Arkansas.
UAMS scientist Samuel G. Mackintosh, Ph.D., received the NIH S10 High-End Instrumentation Award totaling $763,971 to fund the purchase of a mass spectrometer, a piece of equipment used to identify and compare proteins essential for the development of new therapies for cancer and other diseases.
Mackintosh, an Associate Professor in Biochemistry and Molecular Biology, serves as co-director of the UAMS Proteomics Core, a shared resource at the UAMS Winthrop P. Rockefeller Cancer Institute that provides access to technologies, services and scientific consultation for scientists throughout the university, across the country and in Puerto Rico.
“Our goal is to identify new avenues for diagnosis and treatment by comparing proteins present in diseases to proteins present in healthy individuals. The UAMS Proteomics Core supports this research by identifying and quantifying large numbers of proteins from cells, tissues, blood and other biological sources,” said Mackintosh, who also is an associate professor in the UAMS College of Medicine Department of Biochemistry and Molecular Biology.
The core facility is co-directed by Rick Edmondson, Ph.D., associate professor of medicine and director of proteomics. Core staff members include Renny Lan, Aaron Storey, Lisa Orr and Robert Brown.
“Investments by the College of Medicine and Winthrop P. Rockefeller Cancer Institute in the rapidly developing field of mass spectrometry have allowed us to keep up with the advances in the field, ensuring that state-of-the-art technology is available to UAMS researchers,” Mackintosh said.
Three NIH instrument grants have been awarded in Arkansas since 2015, with two going to Mackintosh.
The NIH grant also builds on recent efforts at UAMS to strengthen collaboration between research programs funded by the NIH Institutional Development Award (IDeA) program, which seeks to expand scientific research in 23 historically underfunded states and Puerto Rico.
It also will support proteomics research through three Centers for Biomedical Research Excellence (COBRE), IDeA research centers at UAMS and Arkansas Children’s Hospital that focus on career development for young scientists and expansion of institutional research capabilities.
The COBRE research centers the grant will support focus on three areas:
Other UAMS researchers supporting the instrument grant application include Kevin Raney, Ph.D.; Maria Almeida, Ph.D.; and Srinivas Ayyadevara, Ph.D.
The Bioinformatics and Systems Biology Core, directed by Stephanie Byrum, Ph.D., will play a key role in analyzing data generated by the new mass spectrometer.
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.
