Research Interest Statement:
Research in the Eoff laboratory is focused on understanding molecular mechanisms that allow tolerance of barriers to DNA replication. Some of our ongoing work is centered on the replication stress response in gliomas. The mitigation of replication stress is a barrier to tumorigenesis and a facilitator of chemo-radioresistance. For this reason, our basic research projects have implications for a number of different types of cancer. Moreover, targeted inhibition of replication stress response pathways could lead to new cancer therapeutics. For this reason, we have developed a small-molecule inhibitor of the specialized replication factor DNA polymerase kappa.
“Mechanistic characterization of the cell cycle-dep”
03/01/21 – 02/28/27
National Science Foundation – 1903357
“Replication of G-quadruplex DNA by translesion polymerases”
08/01/19 – 07/31/24
Christov PP, Richie-Jannetta R, Kingsley PJ, [et al., including Eoff RL]. Site-Specific Synthesis of Oligonucleotides Containing 6-Oxo-M1dG, the Genomic Metabolite of M1dG, and Liquid Chromatography-Tandem Mass Spectrometry Analysis of Its In Vitro Bypass by Human Polymerase ?. Chemical research in toxicology. 2021. PMID: 34860508.
Reed MR, Lyle AG, De Loose A, [et al., including Eoff RL]. A Functional Precision Medicine Pipeline Combines Comparative Transcriptomics and Tumor Organoid Modeling to Identify Bespoke Treatment Strategies for Glioblastoma. Cells. 2021 10(12). PMID: 34943910. PMCID: PMC8699481.
Darrigues E, Zhao EH, De Loose A, [et al., including Eoff RL]. Biobanked Glioblastoma Patient-Derived Organoids as a Precision Medicine Model to Study Inhibition of Invasion. International journal of molecular sciences. 2021 22(19). PMID: 34639060. PMCID: PMC8509225.
Hsu CC, Zhang X, Wang G, [et al., including Eoff R]. Inositol serves as a natural inhibitor of mitochondrial fission by directly targeting AMPK. Molecular cell. 2021 81(18):3803-3819.e7. PMID: 34547240. PMCID: PMC8462099.
Urbaniak A, Reed MR, Fil D, [et al., including Eoff RL]. Single and double modified salinomycin analogs target stem-like cells in 2D and 3D breast cancer models. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 2021 141:111815. PMID: 34130123.
Reed MR, Maddukuri L, Ketkar A, [et al., including Eoff RL]. Inhibition of tryptophan 2,3-dioxygenase impairs DNA damage tolerance and repair in glioma cells. NAR cancer. 2021 3(2):zcab014. PMID: 33870196. PMCID: PMC8034706.
Ketkar A, Smith L, Johnson C, [et al., including Eoff RL]. Human Rev1 relies on insert-2 to promote selective binding and accurate replication of stabilized G-quadruplex motifs. Nucleic acids research. 2021 49(4):2065-2084. PMID: 33555350.
Gujarathi S, Zafar MK, Liu X, [et al., including Eoff RL]. A Facile Semisynthesis and Evaluation of Garcinoic Acid and Its Analogs for the Inhibition of Human DNA Polymerase ?. Molecules (Basel, Switzerland). 2020 25(24). PMID: 33322249. PMCID: PMC7763917.
West KL, Kelliher JL, Xu Z, [et al., including Eoff RL]. LC8/DYNLL1 is a 53BP1 effector and regulates checkpoint activation. Nucleic acids research. 2019 47(12):6236-6249. PMID: 30982887. PMCID: PMC6614850.
Ketkar A, Maddukuri L, Penthala NR, [et al., including Eoff RL]. Inhibition of Human DNA Polymerases Eta and Kappa by Indole-Derived Molecules Occurs through Distinct Mechanisms. ACS chemical biology. 2019 14(6):1337-1351. PMID: 31082191. PMCID: PMC7357868.
Zafar MK, Maddukuri L, Ketkar A, [et al., including Eoff RL]. A Small-Molecule Inhibitor of Human DNA Polymerase ? Potentiates the Effects of Cisplatin in Tumor Cells. Biochemistry. 2018 57(7):1262-1273. PMID: 29345908.
Madadi NR, Penthala NR, Ketkar A, [et al., including Eoff RL]. Synthesis and Evaluation of 2-Naphthaleno trans-Stilbenes and Cyanostilbenes as Anticancer Agents. Anti-cancer agents in medicinal chemistry. 2018 18(4):556-564. PMID: 28403783.
Zafar MK, Eoff RL. Translesion DNA Synthesis in Cancer: Molecular Mechanisms and Therapeutic Opportunities. Chemical research in toxicology. 2017 30(11):1942-1955. PMID: 28841374.
Eoff RL, Raney KD. A catch and release program for single-stranded DNA. The Journal of biological chemistry. 2017 292(31):13085-13086. PMID: 28778884. PMCID: PMC5546045.
Ketkar A, Voehler M, Mukiza T, Eoff RL. Residues in the RecQ C-terminal Domain of the Human Werner Syndrome Helicase Are Involved in Unwinding G-quadruplex DNA. The Journal of biological chemistry. 2017 292(8):3154-3163. PMID: 28069813. PMCID: PMC5336152.
Yadlapalli JSK, Ford BM, Ketkar A, [et al., including Eoff RL]. Antinociceptive effects of the 6-O-sulfate ester of morphine in normal and diabetic rats: Comparative role of mu- and delta-opioid receptors. Pharmacological research. 2016 113(Pt A):335-347. PMID: 27637375. PMCID: PMC5107169.
Eddy S, Tillman M, Maddukuri L, [et al., including Eoff RL]. Human Translesion Polymerase ? Exhibits Enhanced Activity and Reduced Fidelity Two Nucleotides from G-Quadruplex DNA. Biochemistry. 2016 55(37):5218-29. PMID: 27525498. PMCID: PMC5113810.
Bostian AC, Eoff RL. Aberrant Kynurenine Signaling Modulates DNA Replication Stress Factors and Promotes Genomic Instability in Gliomas. Chemical research in toxicology. 2016 29(9):1369-80. PMID: 27482758. PMCID: PMC5129620.
Byrd AK, Zybailov BL, Maddukuri L, [et al., including Eoff RL]. Evidence That G-quadruplex DNA Accumulates in the Cytoplasm and Participates in Stress Granule Assembly in Response to Oxidative Stress. The Journal of biological chemistry. 2016 291(34):18041-57. PMID: 27369081. PMCID: PMC5016190.
Madadi NR, Ketkar A, Penthala NR, [et al., including Eoff RL]. Dioxol and dihydrodioxin analogs of 2- and 3-phenylacetonitriles as potent anti-cancer agents with nanomolar activity against a variety of human cancer cells. Bioorganic & medicinal chemistry letters. 2016 26(9):2164-9. PMID: 27017113. PMCID: PMC5930014.
Yeom M, Kim IH, Kim JK, [et al., including Eoff RL]. Effects of Twelve Germline Missense Variations on DNA Lesion and G-Quadruplex Bypass Activities of Human DNA Polymerase REV1. Chemical research in toxicology. 2016 29(3):367-79. PMID: 26914252. PMCID: PMC5116390.
Bostian AC, Maddukuri L, Reed MR, [et al., including Eoff RL]. Kynurenine Signaling Increases DNA Polymerase Kappa Expression and Promotes Genomic Instability in Glioblastoma Cells. Chemical research in toxicology. 2016 29(1):101-8. PMID: 26651356. PMCID: PMC4718841.