A5068509910- Carcinogens and Genotoxicity Assessment
- DNA Repair Mechanisms
- DNA and Nucleic Acid Chemistry
- Epigenetics and DNA Methylation
- RNA modifications and cancer
- Effects and risks of endocrine disrupting chemicals
- Synthesis and Biological Evaluation
- Glutathione Transferases and Polymorphisms
- Genomics and Chromatin Dynamics
- Toxic Organic Pollutants Impact
- Cancer-related gene regulation
- Genomics, phytochemicals, and oxidative stress
- Mass Spectrometry Techniques and Applications
- Advanced biosensing and bioanalysis techniques
- Analytical Chemistry and Chromatography
- Indoor Air Quality and Microbial Exposure
- Nutritional Studies and Diet
- Cancer-related Molecular Pathways
- Genetic factors in colorectal cancer
- Glioma Diagnosis and Treatment
- Advanced Chemical Sensor Technologies
- Metal complexes synthesis and properties
- Cancer therapeutics and mechanisms
- Smoking Behavior and Cessation
- Cancer Genomics and Diagnostics
University of Minnesota
2015-2024
University of Minnesota Medical Center
2015-2024
University of Minnesota System
2022-2024
Shanghai Jiao Tong University
2024
Stockholm University
2024
State Key Laboratory of Environmental Chemistry and Ecotoxicology
2024
Research Center for Eco-Environmental Sciences
2024
Twin Cities Orthopedics
2012-2023
Masonic Cancer Center
2002-2019
Minneapolis Institute of Arts
2018
ConspectusNoncovalent DNA–protein interactions are at the heart of normal cell function. In eukaryotic cells, genomic DNA is wrapped around histone octamers to allow for chromosomal packaging in nucleus. Binding regulatory protein factors directs replication, controls transcription, and mediates cellular responses damage. Because their fundamental significance all processes involving DNA, dynamic required survival, disruption likely have serious biological consequences.DNA–protein...
Glioblastoma (GBM) is often treated with the cytotoxic drug temozolomide, but disease inevitably recurs in a drug-resistant form after initial treatment. Here, we report that GBM cells, even modest decrease mismatch repair (MMR) components MSH2 and MSH6 have profound effects on temozolomide sensitivity. RNAi-mediated attenuation of showed such decreases provided an unexpectedly strong mechanism resistance. In mouse xenograft model human GBM, small changes were sufficient to suppress...
Abstract 5‐Formylcytosine (5fC) is an endogenous DNA modification frequently found within regulatory elements of mammalian genes. Although 5fC oxidation product 5‐methylcytosine (5mC), the two epigenetic marks show distinct genome‐wide distributions and protein affinities, suggesting that they perform different functions in signaling. A unique feature presence a potentially reactive aldehyde group its structure. Herein, we bases readily form Schiff‐base conjugates with Lys side chains...
DNA-protein crosslinks (DPCs) are large cytotoxic DNA lesions that form following exposure to chemotherapeutic drugs and environmental chemicals. Nucleotide excision repair (NER) homologous recombination (HR) promote survival DPC-inducing agents. However, it is not known how cells recognize DPC lesions, or what mechanisms selectively target these respective pathways. To address questions, we examined recognition by transfecting a synthetic lesion comprised of the human oxoguanine glycosylase...
A major DNA oxidation product, 2,2-diamino-4-[(2-deoxy-beta-D-erythro-pentofuranosyl)amino]-5(2H)-oxazolone (oxazolone), can be generated either directly by of dG or as a secondary product with an intermediate 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxo-dG). Site-specific mutagenesis studies indicate that oxazolone is strongly mispairing lesion, inducing approximately 10-fold more mutations than 8-oxo-dG. While 8-oxo-dG undergoes facile further oxidation, appears to stable final guanine and,...
Nitrogen mustards are antitumor agents used clinically for the treatment of a variety neoplastic conditions. The biological activity these compounds is typically attributed to their ability induce DNA−DNA cross-links. However, nitrogen able produce other lesions, including DNA−protein cross-links (DPCs). DPCs induced by not well-characterized because structural complexity and insufficient specificity sensitivity previously available experimental methodologies. In present work, affinity...
1,3-Butadiene (BD) is an important industrial and environmental chemical classified as a human carcinogen based on epidemiologic studies in occupationally exposed workers animal laboratory rats mice. BD metabolically activated to three epoxides that can react with nucleophilic sites biomolecules. Among these, 1,2,3,4-diepoxybutane (DEB) considered the ultimate due its high genotoxicity mutagenicity attributed ability form DNA-DNA cross-links. Our has developed quantitative high-performance...
Antitumor nitrogen mustards, such as bis(2-chloroethyl)methylamine (mechlorethamine), are useful chemotherapeutic agents with a long history of clinical application. The antitumor effects mustards attributed to their ability induce DNA-DNA and DNA-protein cross-links (DPCs) that block DNA replication. In the present work, mass spectrometry-based methodology was employed characterize in vivo cross-linking following treatment human fibrosarcoma (HT1080) cells cytotoxic concentrations...
TET enzymes convert 5-methylcytosine to 5-hydroxymethylcytosine and higher oxidized derivatives. TETs stably associate with are post-translationally modified by the nutrient-sensing enzyme OGT, suggesting a connection between metabolism epigenome. Here, we show for first time that modification OGT enhances TET1 activity in vitro. We identify domain is necessary sufficient binding report point mutation disrupts TET1-OGT interaction. this interaction rescue hematopoetic stem cell production...
DNA–protein cross-links (DPCs) are bulky, helix-distorting DNA lesions that form in the genome upon exposure to common antitumor drugs, environmental/occupational toxins, ionizing radiation, and endogenous free-radical-generating systems. As a result of their considerable size pronounced effects on interactions, DPCs can interfere with replication, transcription, repair, potentially leading mutagenesis, genotoxicity, cytotoxicity. However, biological consequences these ubiquitous not fully...
N,N-Bis-(2-chloroethyl)-phosphorodiamidic acid (phosphoramide mustard, PM) and N,N-bis-(2-chloroethyl)-amine (nornitrogen NOR) are the two biologically active metabolites of cyclophosphamide, a DNA alkylating drug commonly used to treat lymphomas, breast cancer, certain brain cancers, autoimmune diseases. PM NOR reactive bis-electrophiles capable cross-linking cellular biomolecules form covalent DNA-DNA DNA-protein cross-links (DPCs). In present work, mass spectrometry-based proteomics...
// Jiuxia Pang 1 , Na Shen Fei Yan Zhao Liping Dou 1, 2 Lai-Chu Wu 3 Christopher L. Seiler 4 Li Yu Ke Yang 5 Veronika Bachanova 6 Eric Weaver 7 Natalia Y. Tretyakova Shujun Liu The Hormel Institute, University of Minnesota, Austin, MN 55912, USA Department Hematology, Chinese PLA General Hospital, Medical School PLA, Beijing 100853, China Biological Chemistry and Pharmacology, Ohio State University, Columbus, OH 43021, Medicinal Chemistry, Minneapolis, 55455, Chongqing Engineering Research...
Significance DNA modification gives rise to diverse outcomes, including cancer and cell death. Understanding the chemical biochemical effects of contributes fundamental understanding etiology treatment cancer. 2′-Deoxyguanosine methylation at N7 position (MdG) is a major mechanism action some alkylating agents. We examined MdG in nucleosome core particles (NCPs). Abasic site formation from suppressed NCPs. Furthermore, histone proteins form cross-links [DNA–protein (DPCs)], deleterious type...
Objectives/Goals: The bromodomain PHD finger transcription factor (BPTF) is an oncogenic driver of neuroblastoma. Our objective to pioneer the discovery first class chemical compounds that engage BPTF and inhibit its biological function in cellulo, thereby establishing first-in-class probes for this epigenetic reader. Methods/Study Population: previous work has identified a collection small molecules vitro. Following structure–activity relationships analysis, candidates will be used...
1,3-Butadiene (BD) is a high-volume chemical used in the production of rubber and plastic. BD potent carcinogen mice much weaker rats, has been classified as probable human carcinogen. Upon metabolic activation vivo, it forms DNA-reactive metabolites, 1,2-epoxy-3-butene (EB), 1,2:3,4-diepoxybutane (DEB), 3,4-epoxy-1,2-butanediol (EBD). The molecular dosimetry N-7 guanine adduct formation by these metabolites liver, lung, kidney B6C3F1 F344 rats exposed to 0, 20, 62.5, or 625 ppm was studied....
8-Oxoguanine (8-oxo-G) is one of the most common DNA lesions present in normal tissues due to exposure reactive oxygen species. Studies at this and other laboratories suggest that 8-oxo-G highly susceptible secondary oxidation, making it a likely target for endogenous oxidizing agents, such as peroxynitrite (ONOO-). Synthetic oligonucleotides containing 8-oxoguanine were treated with ONOO-, reaction products analyzed by liquid chromatography/electrospray ionization mass spectrometry...
1,3-Butadiene (BD) is a high volume industrial chemical which known as multi-site rodent carcinogen and classified probable human carcinogen. Covalent interactions of the reactive epoxy metabolites BD with DNA lead to formation adducts may cause mutations tumor formation. In present work, liquid chromatography/electrospray ionization tandem mass spectrometry (LC/ESI-MS/MS) was employed for analyses BD-induced in vitro vivo. Selected reaction monitoring (SRM) using fragmentation [M+H]+ ions...
The mutagenicity of a prominent tobacco carcinogen, benzo[a]pyrene (B[a]P), is believed to result from chemical reactions between its diol epoxide metabolite, (+)-anti-7r,8t-dihydroxy-c9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPDE), and DNA, producing promutagenic lesions, e.g., (+)-trans-anti-7R,8S,9S-trihydroxy-10S-(N2-deoxyguanosyl)-7,8,9,10-tetrahydrobenzo[a]pyrene (N2-BPDE-dG). Previous studies used the DNA repair enzyme UvrABC endonuclease in combination with ligation-mediated PCR...
1,2,3,4-diepoxybutane (DEB) is a strongly genotoxic diepoxide hypothesized to be the ultimate carcinogenic metabolite of common industrial chemical and environmental carcinogen 1,3-butadiene. DEB bis-electrophile capable cross-linking cellular biomolecules form DNA-DNA DNA-protein cross-links (DPCs), which are thought play central role in its biological activity. Previous studies with recombinant proteins have shown that outcomes DEB-induced DPCs influenced by protein identities. The present...