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Articles 1 - 19 of 19
Full-Text Articles in Biochemistry, Biophysics, and Structural Biology
Computational Analysis Of O6-Methylated Guanine And Thioguanine Complexes, Kirsten Stinson, Michael Bowman
Computational Analysis Of O6-Methylated Guanine And Thioguanine Complexes, Kirsten Stinson, Michael Bowman
Lux et Fides: A Journal for Undergraduate Christian Scholars
DNA methylation occurring on the O6 position of guanine has been linked to the formation of cancer. DNA complexes with O6-methylated guanine have been studied experimentally, yet questions remain concerning the carcinogenic properties of O6-methylguanine. This present research explored the interaction between O6-methylguanine and its potential nucleobase pairs of cytosine and adenine in hopes of elucidating the mutagenic characteristics of O6-methylguanine. A variety of computational methods including Density Functional Theory (DFT), Symmetry Adapted Perturbation Theory (SAPT), Noncovalent Interaction (NCI) analysis, and Natural Bond Orbital (NBO) analysis were employed to comprehensively probe …
Discovery Of A Small-Molecule Inhibitor That Traps Polθ On Dna And Synergizes With Parp Inhibitors, William Fried, Mrityunjay Tyagi, Leonid Minakhin, Gurushankar Chandramouly, Taylor Tredinnick, Mercy Ramanjulu, William Auerbacher, Marissa L Calbert, Timur Rusanov, Trung Hoang, Nikita Borisonnik, Robert Betsch, John Krais, Yifan Wang, Umeshkumar Vekariya, John Gordon, George Morton, Tatiana Kent, Tomasz Skorski, Neil Johnson, Wayne Childers, Xiaojiang Chen, Richard Pomerantz
Discovery Of A Small-Molecule Inhibitor That Traps Polθ On Dna And Synergizes With Parp Inhibitors, William Fried, Mrityunjay Tyagi, Leonid Minakhin, Gurushankar Chandramouly, Taylor Tredinnick, Mercy Ramanjulu, William Auerbacher, Marissa L Calbert, Timur Rusanov, Trung Hoang, Nikita Borisonnik, Robert Betsch, John Krais, Yifan Wang, Umeshkumar Vekariya, John Gordon, George Morton, Tatiana Kent, Tomasz Skorski, Neil Johnson, Wayne Childers, Xiaojiang Chen, Richard Pomerantz
Department of Biochemistry and Molecular Biology Faculty Papers
The DNA damage response (DDR) protein DNA Polymerase θ (Polθ) is synthetic lethal with homologous recombination (HR) factors and is therefore a promising drug target in BRCA1/2 mutant cancers. We discover an allosteric Polθ inhibitor (Polθi) class with 4-6 nM IC50 that selectively kills HR-deficient cells and acts synergistically with PARP inhibitors (PARPi) in multiple genetic backgrounds. X-ray crystallography and biochemistry reveal that Polθi selectively inhibits Polθ polymerase (Polθ-pol) in the closed conformation on B-form DNA/DNA via an induced fit mechanism. In contrast, Polθi fails to inhibit Polθ-pol catalytic activity on A-form DNA/RNA in which the enzyme binds in …
Chemical Synthesis Of Sensitive Dna, Komal Chillar
Chemical Synthesis Of Sensitive Dna, Komal Chillar
Dissertations, Master's Theses and Master's Reports
Over the past decades, researchers have tried various chemical methods to synthesize modified oligodeoxynucleotides (ODNs, i.e. short segments of DNAs). Traditional ODN synthesis methods require strong basic, and nucleophilic conditions for the deprotection and cleavage of the ODN from the solid support. However, the sensitive ODNs containing labile functionalities are vulnerable to such harsh conditions. Sensitive ODNs have a wide range of applications in research and pharmaceuticals. To synthesize sensitive ODNs, researchers devised different strategies but no practical methods have been developed. To overcome these challenges, we developed alkyl Dim alkyl Dmoc technology. This innovative technology uses weakly basic and …
Dpc29 Promotes Post-Initiation Mitochondrial Translation In Saccharomyces Cerevisiae, Kyle A. Hubble, Michael F. Henry
Dpc29 Promotes Post-Initiation Mitochondrial Translation In Saccharomyces Cerevisiae, Kyle A. Hubble, Michael F. Henry
Rowan-Virtua School of Osteopathic Medicine Faculty Scholarship
Mitochondrial ribosomes synthesize essential components of the oxidative phosphorylation (OXPHOS) system in a tightly regulated process. In the yeast Saccharomyces cerevisiae, mitochondrial mRNAs require specific translational activators, which orchestrate protein synthesis by recognition of their target gene's 5'-untranslated region (UTR). Most of these yeast genes lack orthologues in mammals, and only one such gene-specific translational activator has been proposed in humans-TACO1. The mechanism by which TACO1 acts is unclear because mammalian mitochondrial mRNAs do not have significant 5'-UTRs, and therefore must promote translation by alternative mechanisms. In this study, we examined the role of the TACO1 orthologue in yeast. We …
Investigating Factors That Affect Hiv-1 Capsid Stability, Max Mao, Joshua Temple
Investigating Factors That Affect Hiv-1 Capsid Stability, Max Mao, Joshua Temple
The Yale Undergraduate Research Journal
TKH HIV caSVLd, a SURWHLQ VKHOO cRPSRVHd RI PRQRPHULc XQLWV RI CA, IRUPV a IXOOHUHQH cRQH WKaW SURWHcWV HIV¶V YLUaO JHQRPH aQd enzymes during infection. I am interested in elucidating the factors that influence stability of the capsid shell and capturing the structural interactions between HIV capsid, host restriction factors, and small molecules using biochemical and structural biology techniques. HIV capsid shell was broken down and purified into hexamer and pentamer units for in vitro study. Structural assays were performed using X-ray crystallography and biochemical analysis was performed using pelleting assays. By understanding capsid structure with factors that confer stability, …
Type I Topoisomerases As Potential Targets For Therapeutics, Ahmed Seddek
Type I Topoisomerases As Potential Targets For Therapeutics, Ahmed Seddek
FIU Electronic Theses and Dissertations
DNA topoisomerases are universal enzymes that control the topological features of DNA in all forms of life. This study aims to find potential inhibitors of some of the DNA topoisomerases in bacteria and humans that can be developed into potential therapeutics.
The first aim of this study is to find potential inhibitors of bacterial topoisomerase I that can be developed into antibiotics. There is an urgent need to develop novel antibiotics to overcome the world-wide health crisis of antimicrobial resistance. Virtual screening and biochemical assays were combined to screen thousands of compounds for potential inhibitors of bacterial topoisomerase I. NSC76027 …
Replication Protein A (Rpa) Targeting Of Uracil Dna Glycosylase (Ung2), Derek Chen, Brian P Weiser
Replication Protein A (Rpa) Targeting Of Uracil Dna Glycosylase (Ung2), Derek Chen, Brian P Weiser
Rowan-Virtua Research Day
Replication Protein A (RPA) is a single stranded DNA binding protein which stabilizes ssDNA for replication and repair. One function of RPA is to bind the DNA repair enzyme uracil DNA glycosylase (UNG2) and direct its activity towards ssDNA dsDNA junctions.
UNG2 removes uracil bases from DNA which can appear through dUMP misincorporation or through cytosine deamination. If uracil is present instead of a cytosine, then the original GC pair becomes a GU pair. The uracil will then base pair to adenine in the replicated daughter strand. This results in a GC → AT mutation that could contribute to cancer …
Quantifying Anticancer Drug Doxorubicin Binding To Dna Using Optical Tweezers, Zachary Ells
Quantifying Anticancer Drug Doxorubicin Binding To Dna Using Optical Tweezers, Zachary Ells
Honors Program Theses and Projects
Doxorubicin is a successful anticancer drug approved for use in the 1970s and is considered to be one of the most effective cancer treatment methods today. Although Doxorubicin has positive survival statistics it has very negative side effects in many cases. Bleeding from the soles of the palms and feet, along with excruciating pain is often exhibited through the administration of this drug. Based on the preliminary findings utilizing optical tweezers we anticipate that this study will provide critical information about the drug binding mechanism. Single molecule biophysics techniques have provided useful insight into the DNA-binding mechanisms of small molecules. …
N-Terminal Domain Of Human Uracil Dna Glycosylase (Hung2) Promotes Targeting To Uracil Sites Adjacent To Ssdna-Dsdna Junctions, Brian P Weiser, Gaddiel Rodriguez, Philip A Cole, James T Stivers
N-Terminal Domain Of Human Uracil Dna Glycosylase (Hung2) Promotes Targeting To Uracil Sites Adjacent To Ssdna-Dsdna Junctions, Brian P Weiser, Gaddiel Rodriguez, Philip A Cole, James T Stivers
Rowan-Virtua School of Osteopathic Medicine Faculty Scholarship
The N-terminal domain (NTD) of nuclear human uracil DNA glycosylase (hUNG2) assists in targeting hUNG2 to replication forks through specific interactions with replication protein A (RPA). Here, we explored hUNG2 activity in the presence and absence of RPA using substrates with ssDNA-dsDNA junctions that mimic structural features of the replication fork and transcriptional R-loops. We find that when RPA is tightly bound to the ssDNA overhang of junction DNA substrates, base excision by hUNG2 is strongly biased toward uracils located 21 bp or less from the ssDNA-dsDNA junction. In the absence of RPA, hUNG2 still showed an 8-fold excision bias …
Development Of Lc-Ms For The Identification And Characterization Of Non-Adjacent Dna Photoproduct Formation In G-Quadruplex Forming Sequences, Claudia Posadas
Development Of Lc-Ms For The Identification And Characterization Of Non-Adjacent Dna Photoproduct Formation In G-Quadruplex Forming Sequences, Claudia Posadas
Arts & Sciences Electronic Theses and Dissertations
Ultraviolet light is well known to induce cyclobutane pyrimidine dimers (CPD) and pyrimidine (6–4) pyrimidone photoproducts in duplex DNA, which interfere with DNA replication and transcription. Recently, a new class of DNA photoproducts known as anti cyclobutanepyrimidine dimers have been discovered, which form in G-quadruplex forming sequences in solution. G-quadruplex structures have been proposed to form in human DNA telomeres and certain promoters in vivo but evidence for their existence has been lacking. Since anti-cyclobutante pyrimidine dimers have been shown to form in G-quadruplex forming sequences, their formation in irradiated human cells could be used to confirm the existence …
Quaternary Interactions And Supercoiling Modulate The Cooperative Dna Binding Of Agt, Manana Melikishvili, Michael G. Fried
Quaternary Interactions And Supercoiling Modulate The Cooperative Dna Binding Of Agt, Manana Melikishvili, Michael G. Fried
Center for Structural Biology Faculty Publications
Human O6-alkylguanine-DNA alkyltransferase (AGT) repairs mutagenic O6-alkylguanine and O4-alkylthymine adducts in single-stranded and duplex DNAs. The search for these lesions, through a vast excess of competing, unmodified genomic DNA, is a mechanistic challenge that may limit the repair rate in vivo. Here, we examine influences of DNA secondary structure and twist on protein–protein interactions in cooperative AGT complexes formed on lesion-free DNAs that model the unmodified parts of the genome. We used a new approach to resolve nearest neighbor (nn) and long-range (lr) components from the ensemble-average cooperativity, ωave. We found …
Aptameric Sensors: In Vitro Selection Of Dna That Binds Bromocresol Purple, Derek B. Miller
Aptameric Sensors: In Vitro Selection Of Dna That Binds Bromocresol Purple, Derek B. Miller
Honors Undergraduate Theses
Aptamers being used as sensors is an emerging field that has capabilities of being tomorrow’s diagnostic tools. As aptameric sensors have become more popular, their visualization systems have been limited. The majority of today’s aptameric sensors require expensive machinery such as a fluorometer in order to visualize results. We propose a system that will cut the need for instrumentation and be detected via the naked eye. With the selection of an aptamer to bind the pH indicating dye bromocresol purple (BCP) this may be achieved. When rendered active, the binding towards BCP will facilitate a color change from yellow to …
Large-Scale Identification Of Chemically Induced Mutations In Drosophila Melanogaster., Nele A Haelterman, Lichun Jiang, Yumei Li, Vafa Bayat, Hector Sandoval, Berrak Ugur, Kai Li Tan, Ke Zhang, Danqing Bei, Bo Xiong, Wu-Lin Charng, Theodore Busby, Adeel Jawaid, Gabriela David, Manish Jaiswal, Koen J T Venken, Shinya Yamamoto, Rui Chen, Hugo J Bellen
Large-Scale Identification Of Chemically Induced Mutations In Drosophila Melanogaster., Nele A Haelterman, Lichun Jiang, Yumei Li, Vafa Bayat, Hector Sandoval, Berrak Ugur, Kai Li Tan, Ke Zhang, Danqing Bei, Bo Xiong, Wu-Lin Charng, Theodore Busby, Adeel Jawaid, Gabriela David, Manish Jaiswal, Koen J T Venken, Shinya Yamamoto, Rui Chen, Hugo J Bellen
Faculty Publications
Forward genetic screens using chemical mutagens have been successful in defining the function of thousands of genes in eukaryotic model organisms. The main drawback of this strategy is the time-consuming identification of the molecular lesions causative of the phenotypes of interest. With whole-genome sequencing (WGS), it is now possible to sequence hundreds of strains, but determining which mutations are causative among thousands of polymorphisms remains challenging. We have sequenced 394 mutant strains, generated in a chemical mutagenesis screen, for essential genes on the Drosophila X chromosome and describe strategies to reduce the number of candidate mutations from an average of …
Metagenomic Identification Of A Novel Salt Tolerance Gene From The Human Gut Microbiome Which Encodes A Membrane Protein With Homology To A Brp/Blh-Family Beta-Carotene 15,15'-Monooxygenase, Eamonn P. Culligan, Roy D. Sleator, Julian R. Marchesi, Colin Hill
Metagenomic Identification Of A Novel Salt Tolerance Gene From The Human Gut Microbiome Which Encodes A Membrane Protein With Homology To A Brp/Blh-Family Beta-Carotene 15,15'-Monooxygenase, Eamonn P. Culligan, Roy D. Sleator, Julian R. Marchesi, Colin Hill
Department of Biological Sciences Publications
The human gut microbiome consists of at least 3 million non-redundant genes, 150 times that of the core human genome. Herein, we report the identification and characterisation of a novel stress tolerance gene from the human gut metagenome. The locus, assigned brpA, encodes a membrane protein with homology to a brp/blh-family β-carotene monooxygenase. Cloning and heterologous expression of brpA in Escherichia coli confers a significant salt tolerance phenotype. Furthermore, when cultured in the presence of exogenous β-carotene, cell pellets adopt a red/orange pigmentation indicating the incorporation of carotenoids in the cell membrane.
Is Sudden Infant Death Syndrome Associated With Helicobacter Pylori Infection In Children?, Yoram Elitsur, William Btriest, Zia Sabet, Cheryl Neace, Chuancang Jiang, Eapen Thomas
Is Sudden Infant Death Syndrome Associated With Helicobacter Pylori Infection In Children?, Yoram Elitsur, William Btriest, Zia Sabet, Cheryl Neace, Chuancang Jiang, Eapen Thomas
Yoram Elitsur
Helicobacter pylori infection has recently been implicated in the pathogenesis of sudden infant death syndrome (SIDS). We investigated this association. Twenty-five pairs of gastric and tracheal tissue specimens obtained from autopsies of 25 children with previous diagnoses of SIDS were available for this study. The presence of H. pylori organisms was evaluated by three different methods: histology (hematoxylin-eosin or Giemsa staining), immunohistochemistry, and nested polymerase chain reaction technique. We were unable to confirm the presence of H. pylori organisms by the first two methods. H. pylori DNA was identified by nested polymerase chain reaction in six different tissue specimens (stomach, …
Atf4 Is An Oxidative Stress–Inducible, Prodeath Transcription Factor In Neurons In Vitro And In Vivo, Philipp Lange, Juan Chavez, John T. Pinto, Giovanni Coppola, Chiao-Wang Sun, Tim Townes, Rajiv Ratan
Atf4 Is An Oxidative Stress–Inducible, Prodeath Transcription Factor In Neurons In Vitro And In Vivo, Philipp Lange, Juan Chavez, John T. Pinto, Giovanni Coppola, Chiao-Wang Sun, Tim Townes, Rajiv Ratan
NYMC Faculty Publications
Oxidative stress is pathogenic in neurological diseases, including stroke. The identity of oxidative stress-inducible transcription factors and their role in propagating the death cascade are not well known. In an in vitro model of oxidative stress, the expression of the bZip transcription factor activating transcription factor 4 (ATF4) was induced by glutathione depletion and localized to the promoter of a putative death gene in neurons. Germline deletion of ATF4 resulted in a profound reduction in oxidative stress-induced gene expression and resistance to oxidative death. In neurons, ATF4 modulates an early, upstream event in the death pathway, as resistance to oxidative …
Electrical Detection Of The Temperature Induced Melting Transition Of A Dna Hairpin Covalently Attached To Gold Interdigitated Microelectrodes, Greg P. Brewood, Yaswanth Rangineni, Daniel J. Fish, Ashwini Bhandiwad, David R. Evans, Raj Solanki, Albert S. Benight
Electrical Detection Of The Temperature Induced Melting Transition Of A Dna Hairpin Covalently Attached To Gold Interdigitated Microelectrodes, Greg P. Brewood, Yaswanth Rangineni, Daniel J. Fish, Ashwini Bhandiwad, David R. Evans, Raj Solanki, Albert S. Benight
Chemistry Faculty Publications and Presentations
The temperature induced melting transition of a self-complementary DNA strand covalently attached at the 5' end to the surface of a gold interdigitated microelectrode (GIME) was monitored in a novel, label-free, manner. The structural state of the hairpin was assessed by measuring four different electronic properties of the GIME (capacitance, impedance, dissipation factor and phase angle) as a function of temperature from 25 degrees C to 80 degrees C. Consistent changes in all four electronic properties of the GIME were observed over this temperature range, and attributed to the transition of the attached single-stranded DNA (ssDNA) from an intramolecular, folded …
Cationic Surfactant Mediated Hybridization And Hydrophobization Of Dna Molecules At The Liquid/Liquid Interface And Their Phase Transfer, Murali Sastry, Ashavani Kumar, Mrunalini Pattarkine, Vidya Ramakrishnan, Krishna N. Ganesh
Cationic Surfactant Mediated Hybridization And Hydrophobization Of Dna Molecules At The Liquid/Liquid Interface And Their Phase Transfer, Murali Sastry, Ashavani Kumar, Mrunalini Pattarkine, Vidya Ramakrishnan, Krishna N. Ganesh
Faculty Works
Hybridization of complementary oligonucleotides mediated by a cationic surfactant at the water/hexane interface leads to hydrophobic, double-helical DNA which may be readily phase transferred to the organic phase and cast into thin films on solid substrates.
An Analysis Of Mitochondrial Dna In Rett Syndrome And Other Neurodegenerative Disorders, Catherine Erickson Burgess
An Analysis Of Mitochondrial Dna In Rett Syndrome And Other Neurodegenerative Disorders, Catherine Erickson Burgess
Theses and Dissertations in Biomedical Sciences
Mitochondrial dysfunction resulting from mutations on mitochondrial DNA (mtDNA) is being recognized in a growing spectrum of diseases. These diseases, resulting from single base mutations, large deletions, or insertions, have been largely neuromuscular in origin. However, as an understanding of the effects of mtDNA mutations progresses, attention is now focusing on neurodegenerative diseases. Rett Syndrome (RS), a progressive neurodegenerative disease with predominantly female cases, demonstrates morphologic mitochondrial changes, mitochondrial enzyme deficiencies and maternal inheritance (characteristic of mtDNA diseases). No investigation of mtDNA involvement has been previously conducted and, to date, no biological marker exists for this disorder.
Our preliminary studies …