A5041935136- DNA Repair Mechanisms
- DNA and Nucleic Acid Chemistry
- Epigenetics and DNA Methylation
- Genomics and Chromatin Dynamics
- Chemical Reactions and Isotopes
- RNA modifications and cancer
- Chemical Synthesis and Analysis
- Tryptophan and brain disorders
- Biochemical and Molecular Research
- Bipolar Disorder and Treatment
- CRISPR and Genetic Engineering
- Genomics, phytochemicals, and oxidative stress
- Animal Genetics and Reproduction
- Bioactive Compounds and Antitumor Agents
- Cancer therapeutics and mechanisms
- Free Radicals and Antioxidants
- Virus-based gene therapy research
- Enzyme Structure and Function
- Folate and B Vitamins Research
- Mitochondrial Function and Pathology
- Synthesis and Characterization of Heterocyclic Compounds
- Glycosylation and Glycoproteins Research
- Ethics in Clinical Research
- Stress Responses and Cortisol
- Cell death mechanisms and regulation
University of Maryland, Baltimore
2016-2024
Institute for Bioscience and Biotechnology Research
2017
University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center
2017
Thymine DNA Glycosylase (TDG) is a base excision repair enzyme functioning in and epigenetic regulation. TDG removes thymine from mutagenic G·T mispairs arising deamination of 5-methylcytosine (mC), it processes other deamination-derived lesions including uracil (U). Essential for demethylation, excises 5-formylcytosine 5-carboxylcytosine, derivatives mC generated by Tet (ten-eleven translocation) enzymes. Here, we report structural functional studies TDG82-308, new construct containing 29...
Thymine DNA glycosylase (TDG) is a base excision repair enzyme with key functions in epigenetic regulation. Performing critical step pathway for active demethylation, TDG removes 5-formylcytosine and 5-carboxylcytosine, oxidized derivatives of 5-methylcytosine that are generated by TET (ten-eleven translocation) enzymes. We determined crystal structure bound to noncleavable (2'-fluoroarabino) analogue 5-formyldeoxycytidine flipped into its site, revealing how it recognizes hydrolytically...
Multimeric naphthoquinones are redox-active compounds that exhibit antineoplastic, antiprotozoal, and antiviral activities. Due to their multimodal effect on perturbation of cellular oxidative state, these hold great potential as therapeutic agents against highly proliferative neoplastic cells. In our previous work, we developed a series novel dimeric showed they were selectively cytotoxic human acute myeloid leukemia (AML), breast prostate cancer cell lines. We subsequently identified the...
AP endonuclease 1 (APE1) processes DNA lesions including apurinic/apyrimidinic sites and 3´-blocking groups, mediating base excision repair single strand break repair. Much effort has focused on developing specific inhibitors of APE1, which could have important applications in basic research potentially lead to clinical anticancer agents. We used structural, biophysical, biochemical methods characterize several reported inhibitors, 7-nitroindole-2-carboxylic acid (CRT0044876), given its...
5-Methylcytosine (mC) is an epigenetic mark that written by methyltransferases, erased through passive and active mechanisms, impacts transcription, development, diseases including cancer, aging. Active DNA demethylation involves TET-mediated stepwise oxidation of mC to 5-hydroxymethylcytosine, 5-formylcytosine (fC), or 5-carboxylcytosine (caC), excision fC caC thymine glycosylase (TDG), subsequent base repair. Many elements this essential process are poorly defined, TDG caC. To address...
Selective targeting of the oxidative state, which is a tightly balanced fundamental cellular property, an attractive strategy for developing novel anti-leukemic chemotherapeutics with potential applications in treatment acute myeloid leukemia (AML), molecularly heterogeneous disease. Dimeric naphthoquinones (BiQs) ability to undergo redox cycling and generate reactive oxygen species (ROS) cancer cells are class compounds unique characteristics that make them excellent candidates be tested...
Oxidation of DNA bases generates mutagenic and cytotoxic lesions that are implicated in cancer other diseases. Oxidative base lesions, including 7,8-dihydro-8-oxoguanine, typically removed through excision repair. In addition, oxidized deoxynucleotides such as 8-oxo-dGTP depleted by sanitizing enzymes to preclude incorporation. While pathways counter threats posed 7,8-dihydro-8-oxoguanine well characterized, mechanisms protecting against the major adenine oxidation product,...
3-Hydroxyanthranilate 3,4-dioxygenase (3HAO) is an enzyme in the microglial branch of kynurenine pathway tryptophan degradation. 3HAO a non-heme iron-containing, ring-cleaving extradiol dioxygenase that catalyzes addition both atoms O2 to metabolite 3-hydroxyanthranilic acid (3-HANA) form quinolinic (QUIN). QUIN highly potent excitotoxin has been implicated number neurodegenerative conditions, making target for pharmacological downregulation. Here, first crystal structure human with native...
The Rad9-Rad1-Hus1 checkpoint clamp activates the DNA damage response and promotes repair. loading on central channel of complex is required to execute its biological functions. Because Rad9A has highest affinity among three subunits, we determined domains functional residues human that are critical for interaction. N-terminal globular domain (residues 1–133) had 3.7-fold better binding than C-terminal 134–266) 1-266 . binds 16-, 60-, 30-fold 1-133 , 134-266 94-266 respectively, indicating...
The base excision repair enzyme thymine DNA glycosylase (TDG) protects against mutations by removing or uracil from guanine mispairs and functions in active demethylation excising 5-formylcytosine (fC) 5-carboxylcytosine (caC). Post-translational modification of TDG SUMO (small ubiquitin-like modifier) reduces its activity but the mechanism remains unclear. We investigated this problem using biochemical biophysical approaches a construct comprising residues 82 to 340 (of 410) that includes...
5-methylcytosine (mC) is a prominent DNA modification that signals for transcriptional silencing, and this epigenetic mark erased through multi-step pathway involving TET (ten-eleven translocation) base excision repair (BER) enzymes.Faithful regulation of cytosine methylation essential development, aberrant implicated in cancer other diseases.TET enzymes initiate the process active demethylation, by oxidizing mC to give three potential oxy-mC products, 5-hydroxymethylcytosine (hmC),...