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Elucidating Nucleic Acid Binding Properties Of Polycomb Repressive Complex 2, Richard D. Paucek 2017 University of Colorado Boulder

Elucidating Nucleic Acid Binding Properties Of Polycomb Repressive Complex 2, Richard D. Paucek

Undergraduate Honors Theses

Polycomb Repressive Complex 2 (PRC2) is a histone methyltransferase that specifically deposits mono-, di-, and tri-methylation marks onto chromatin. This activity triggers epigenetic silencing, a process critical for cell differentiation and maintenance of cellular identity. In mammalian cells, how PRC2 is recruited to target sites is unknown, but it is speculated that RNA, histone modifications, nucleosome architecture, and DNA elements all possess direct or indirect recruitment and regulatory roles. However, the relative binding affinity of PRC2 for these diverse biological substrates remains poorly understood. In the present study, the binding affinity of PRC2 for various RNAs and nucleosomes were tested ...


High Epstein-Barr Virus Load And Genomic Diversity Are Associated With Generation Of Gp350-Specific Neutralizing Antibodies Following Acute Infectious Mononucleosis, Eric R. Weiss, Galit Alter, Javier Gordon Ogembo, Jennifer L. Henderson, Barbara Tabak, Yasin Bakis, Mohan Somasundaran, Manuel Garber, Liisa K. Selin, Katherine Luzuriaga 2016 University of Massachusetts Medical School

High Epstein-Barr Virus Load And Genomic Diversity Are Associated With Generation Of Gp350-Specific Neutralizing Antibodies Following Acute Infectious Mononucleosis, Eric R. Weiss, Galit Alter, Javier Gordon Ogembo, Jennifer L. Henderson, Barbara Tabak, Yasin Bakis, Mohan Somasundaran, Manuel Garber, Liisa K. Selin, Katherine Luzuriaga

Garber Lab Publications

The Epstein-Barr virus (EBV) gp350 glycoprotein interacts with the cellular receptor to mediate viral entry and is thought to be the major target for neutralizing antibodies. To better understand the role of EBV-specific antibodies in the control of viral replication and the evolution of sequence diversity, we measured EBV gp350-specific antibody responses and sequenced the gp350 gene in samples obtained from individuals experiencing primary EBV infection (acute infectious mononucleosis [AIM]) and again 6 months later (during convalescence [CONV]). EBV gp350-specific IgG was detected in the sera of 17 (71%) of 24 individuals at the time of AIM and all 24 ...


Akap12 Mediates Pka-Induced Phosphorylation Of Atr To Enhance Nucleotide Excision Repair, Stuart G. Jarrett, Erin M. Wolf Horrell, John A. D'Orazio 2016 University of Kentucky

Akap12 Mediates Pka-Induced Phosphorylation Of Atr To Enhance Nucleotide Excision Repair, Stuart G. Jarrett, Erin M. Wolf Horrell, John A. D'Orazio

Markey Cancer Center Faculty Publications

Loss-of-function in melanocortin 1 receptor (MC1R), a GS protein-coupled receptor that regulates signal transduction through cAMP and protein kinase A (PKA) in melanocytes, is a major inherited melanoma risk factor. Herein, we report a novel cAMP-mediated response for sensing and responding to UV-induced DNA damage regulated by A-kinase-anchoring protein 12 (AKAP12). AKAP12 is identified as a necessary participant in PKA-mediated phosphorylation of ataxia telangiectasia mutated and Rad3-related (ATR) at S435, a post-translational event required for cAMP-enhanced nucleotide excision repair (NER). Moreover, UV exposure promotes ATR-directed phosphorylation of AKAP12 at S732, which promotes nuclear translocation of AKAP12–ATR-pS435. This complex ...


The Large Terminase Dna Packaging Motor Grips Dna With Its Atpase Domain For Cleavage By The Flexible Nuclease Domain, Brendan J. Hilbert, Janelle A. Hayes, Nicholas P. Stone, Rui-Gang Xu, Brian A. Kelch 2016 University of Massachusetts Medical School

The Large Terminase Dna Packaging Motor Grips Dna With Its Atpase Domain For Cleavage By The Flexible Nuclease Domain, Brendan J. Hilbert, Janelle A. Hayes, Nicholas P. Stone, Rui-Gang Xu, Brian A. Kelch

University of Massachusetts Medical School Faculty Publications

Many viruses use a powerful terminase motor to pump their genome inside an empty procapsid shell during virus maturation. The large terminase (TerL) protein contains both enzymatic activities necessary for packaging in such viruses: the ATPase that powers DNA translocation and an endonuclease that cleaves the concatemeric genome both at initiation and completion of genome packaging. However, how TerL binds DNA during translocation and cleavage is still mysterious. Here we investigate DNA binding and cleavage using TerL from the thermophilic phage P74-26. We report the structure of the P74-26 TerL nuclease domain, which allows us to model DNA binding in ...


Structures Of Mithramycin Analogues Bound To Dna And Implications For Targeting Transcription Factor Fli1, Caixia Hou, Stevi Weidenbach, Kristin E. Cano, Zhonghua Wang, Prithiba Mitra, Dmitri N. Ivanov, Jürgen Rohr, Oleg V. Tsodikov 2016 University of Kentucky

Structures Of Mithramycin Analogues Bound To Dna And Implications For Targeting Transcription Factor Fli1, Caixia Hou, Stevi Weidenbach, Kristin E. Cano, Zhonghua Wang, Prithiba Mitra, Dmitri N. Ivanov, Jürgen Rohr, Oleg V. Tsodikov

Pharmaceutical Sciences Faculty Publications

Transcription factors have been considered undruggable, but this paradigm has been recently challenged. DNA binding natural product mithramycin (MTM) is a potent antagonist of oncogenic transcription factor EWS–FLI1. Structural details of MTM recognition of DNA, including the FLI1 binding sequence GGA(A/T), are needed to understand how MTM interferes with EWS–FLI1. We report a crystal structure of an MTM analogue MTM SA–Trp bound to a DNA oligomer containing a site GGCC, and two structures of a novel analogue MTM SA–Phe in complex with DNA. MTM SA–Phe is bound to sites AGGG and GGGT on ...


Genome-Wide Mapping Of Uncapped And Cleaved Transcripts Reveals A Role For The Nuclear Mrna Cap-Binding Complex In Cotranslational Rna Decay In Arabidopsis, Xiang Yu, Matthew R. Willmann, Stephen J. Anderson, Brian D. Gregory 2016 University of Pennsylvania

Genome-Wide Mapping Of Uncapped And Cleaved Transcripts Reveals A Role For The Nuclear Mrna Cap-Binding Complex In Cotranslational Rna Decay In Arabidopsis, Xiang Yu, Matthew R. Willmann, Stephen J. Anderson, Brian D. Gregory

Departmental Papers (Biology)

RNA turnover is necessary for controlling proper mRNA levels posttranscriptionally. In general, RNA degradation is via exoribonucleases that degrade RNA either from the 5′ end to the 3′ end, such as XRN4, or in the opposite direction by the multisubunit exosome complex. Here, we use genome-wide mapping of uncapped and cleaved transcripts to reveal the global landscape of cotranslational mRNA decay in the Arabidopsis thaliana transcriptome. We found that this process leaves a clear three nucleotide periodicity in open reading frames. This pattern of cotranslational degradation is especially evident near the ends of open reading frames, where we observe accumulation ...


Prima: A Gene-Centered, Rna-To-Protein Method For Mapping Rna-Protein Interactions, Alex M. Tamburino, Ebru Kaymak, Shaleen Shrestha, Amy D. Holdorf, Sean P. Ryder, Albertha J. M. Walhout 2016 University of Massachusetts Medical School

Prima: A Gene-Centered, Rna-To-Protein Method For Mapping Rna-Protein Interactions, Alex M. Tamburino, Ebru Kaymak, Shaleen Shrestha, Amy D. Holdorf, Sean P. Ryder, Albertha J. M. Walhout

University of Massachusetts Medical School Faculty Publications

Interactions between RNA binding protein (RBP) and mRNAs are critical to post-transcriptional gene regulation. Eukaryotic genomes encode thousands of mRNAs and hundreds of RBPs. However, in contrast to interactions between transcription factors (TFs) and DNA, the interactome between RBPs and RNA has been explored for only a small number of proteins and RNAs. This is largely because the focus has been on using 'protein-centered' (RBP-to-RNA) interaction mapping methods that identify the RNAs with which an individual RBP interacts. While powerful, these methods cannot as of yet be applied to the entire RBPome. Moreover, it may be desirable for a researcher ...


A Common Class Of Transcripts With 5'-Intron Depletion, Distinct Early Coding Sequence Features, And N1-Methyladenosine Modification, Can Cenik, Hon Nian Chua, Guramrit Singh, Abdalla Akef, Michael P. Snyder, Alexander F. Palazzo, Melissa J. Moore, Frederick P. Roth 2016 University of Massachusetts Medical School

A Common Class Of Transcripts With 5'-Intron Depletion, Distinct Early Coding Sequence Features, And N1-Methyladenosine Modification, Can Cenik, Hon Nian Chua, Guramrit Singh, Abdalla Akef, Michael P. Snyder, Alexander F. Palazzo, Melissa J. Moore, Frederick P. Roth

University of Massachusetts Medical School Faculty Publications

Introns are found in 5' untranslated regions (5'UTRs) for 35% of all human transcripts. These 5'UTR introns are not randomly distributed: genes that encode secreted, membrane-bound and mitochondrial proteins are less likely to have them. Curiously, transcripts lacking 5'UTR introns tend to harbor specific RNA sequence elements in their early coding regions. To model and understand the connection between coding-region sequence and 5'UTR intron status, we developed a classifier that can predict 5'UTR intron status with >80% accuracy using only sequence features in the early coding region. Thus, the classifier identifies transcripts with 5' proximal-intron-minus-like-coding ...


Stability And Kinetics Of Dna Pseudoknots: Formation Of T∗A•T Base-Triplets And Their Targeting Reactions, Calliste Steffensmeier 2016 University of Nebraska Medical Center

Stability And Kinetics Of Dna Pseudoknots: Formation Of T∗A•T Base-Triplets And Their Targeting Reactions, Calliste Steffensmeier

Theses & Dissertations

Pseudoknots have been found to play important roles in the biology of RNA. These stem-loop motifs are considered to be very compact and the targeting of their loops with complementary strands is accompanied with lower favorable free energy terms. We used a combination of spectroscopic (UV, CD and fluorescence), calorimetric (DSC, PPC and ITC) and kinetic (SPR) techniques to investigate: 1) Local base-triplet formation in pseudoknots; 2) energetic contributions for the association of pseudoknots with their complementary strands; and 3) the kinetic rates as a function of targeting strand length.

We investigated a set of DNA pseudoknots with sequence: d ...


Assembly Of Nucleic Acid-Based Nanoparticles By Gas-Liquid Segmented Flow Microfluidics, Matthew L. Capek, Ross VerHeul, David H. Thompson 2016 Purdue University

Assembly Of Nucleic Acid-Based Nanoparticles By Gas-Liquid Segmented Flow Microfluidics, Matthew L. Capek, Ross Verheul, David H. Thompson

The Summer Undergraduate Research Fellowship (SURF) Symposium

The development of novel and efficient mixing methods is important for optimizing the efficiency of many biological and chemical processes. Tuning the physical and performance properties of nucleic acid-based nanoparticles is one such example known to be strongly affected by mixing efficiency. The characteristics of DNA nanoparticles (such as size, polydispersity, ζ-potential, and gel shift) are important to ensure their therapeutic potency, and new methods to optimize these characteristics are of significant importance to achieve the highest efficacy. In the present study, a simple segmented flow microfluidics system has been developed to augment mixing of pDNA/bPEI nanoparticles. This DNA ...


Analysis Of The Intricacies Of Substrate Recognition Of High Mobility Group Proteins And Aminoacyl-Trna Synthetases Using Non-Cognate Substrates, Douglas Van Iverson II 2016 University of Southern Mississippi

Analysis Of The Intricacies Of Substrate Recognition Of High Mobility Group Proteins And Aminoacyl-Trna Synthetases Using Non-Cognate Substrates, Douglas Van Iverson Ii

Dissertations

The studies presented in section 1 (Chapters I-IV) focus on the design and development of nucleic acid four-way junctions (4WJs) to target a member of the high mobility group (HMG) proteins, the proinflammatory cytokine high mobility group box 1 protein (HMGB1). In the present study, hybrid PNA-DNA 4WJs based on a model DNA 4WJ were constructed to improve the thermal stability of 4WJs while maintaining strong binding affinity toward HMGB1. An electrophoretic mobility shift assay (EMSA) was used to examine the binding affinity of an isolated DNA binding domain of HMGB1, the HMGB1 b-box (HMGB1b), toward a set of PNA-DNA ...


Rsq: A Statistical Method For Quantification Of Isoform-Specific Structurome Using Transcriptome-Wide Structural Profiling Data, Yunfei Wang, University of Texas at Dallas, Xiaopeng Zhu, Ming Sun, Yong Chen, Michael Q. Zhang, Yiwen Chen, Shikui Tu, Qi Dai, Haozhe Wang, Boyang Bai 2016 University of Texas at Dallas

Rsq: A Statistical Method For Quantification Of Isoform-Specific Structurome Using Transcriptome-Wide Structural Profiling Data, Yunfei Wang, University Of Texas At Dallas, Xiaopeng Zhu, Ming Sun, Yong Chen, Michael Q. Zhang, Yiwen Chen, Shikui Tu, Qi Dai, Haozhe Wang, Boyang Bai

University of Massachusetts Medical School Faculty Publications

The structure of RNA, which is considered to be a second layer of information alongside the genetic code, provides fundamental insights into the cellular function of both coding and non-coding RNAs. Several high-throughput technologies have been developed to profile transcriptome-wide RNA structures, i.e., the structurome. However, it is challenging to interpret the profiling data because the observed data represent an average over different RNA conformations and isoforms with different abundance. To address this challenge, we developed an RNA structurome quantification method (RSQ) to statistically model the distribution of reads over both isoforms and RNA conformations, and thus provide accurate ...


Discordant Expression Of Circulating Microrna From Cellular And Extracellular Sources, Ravi Shah, Kahraman Tanriverdi, Daniel Levy, Martin Larson, Mark B. Gerstein, Eric O. Mick, Joel Rozowsky, Robert Kitchen, Venkatesh Murthy, Ekaterina Mikalev, Jane E. Freedman 2016 Beth Israel Deaconess Medical Center

Discordant Expression Of Circulating Microrna From Cellular And Extracellular Sources, Ravi Shah, Kahraman Tanriverdi, Daniel Levy, Martin Larson, Mark B. Gerstein, Eric O. Mick, Joel Rozowsky, Robert Kitchen, Venkatesh Murthy, Ekaterina Mikalev, Jane E. Freedman

Open Access Articles

MicroRNA (miRNA) expression has rapidly grown into one of the largest fields for disease characterization and development of clinical biomarkers. Consensus is lacking in regards to the optimal sample source or if different circulating sources are concordant. Here, using miRNA measurements from contemporaneously obtained whole blood- and plasma-derived RNA from 2391 individuals, we demonstrate that plasma and blood miRNA levels are divergent and may reflect different biological processes and disease associations.


The Mechanistic Role And Therapeutic Potential Of Microrna-122 In Alcoholic Liver Disease: A Dissertation, Abhishek Satishchandran 2016 University of Massachusetts Medical School

The Mechanistic Role And Therapeutic Potential Of Microrna-122 In Alcoholic Liver Disease: A Dissertation, Abhishek Satishchandran

GSBS Dissertations and Theses

Chronic alcohol use results in accelerated liver injury, leading to alcoholic steatohepatitis, cirrhosis, and hepatocellular carcinoma. However, due to the complex nature of this disease process, a central, druggable mechanism has remained elusive. microRNAs are potent post-transcriptional regulators of gene expression. A single miRNA has the ability to regulate hundreds of pathways simultaneously, defining cellular fate and function. microRNA-122 (miR-122), the most abundant miRNA in hepatocytes, has a demonstrated role as an tumor suppressor, regulator of hepatocyte metabolism, and hepatic differentiation.

In this dissertation I demonstrate the role of miR-122 on alcoholic liver disease (ALD) pathogenesis over four parts. In ...


Micro- And Nanoparticulates For Dna Vaccine Delivery, Eric Farris, Deborah M. Brown, Amanda Ramer-Tait, Angela K. Pannier 2016 University of Nebraska–Lincoln

Micro- And Nanoparticulates For Dna Vaccine Delivery, Eric Farris, Deborah M. Brown, Amanda Ramer-Tait, Angela K. Pannier

Biological Systems Engineering: Papers and Publications

DNA vaccination has emerged as a promising alternative to traditional protein-based vaccines for the induction of protective immune responses. DNA vaccines offer several advantages over traditional vaccines, including increased stability, rapid and inexpensive production, and flexibility to produce vaccines for a wide variety of infectious diseases. However, the immunogenicity of DNA vaccines delivered as naked plasmid DNA is often weak due to degradation of the DNA by nucleases and inefficient delivery to immune cells. Therefore, biomaterial-based delivery systems based on micro- and nanoparticles that encapsulate plasmid DNA represent the most promising strategy for DNA vaccine delivery. Microparticulate delivery systems allow ...


Identification Of Potential Drug Targets In Cancer Signaling Pathways Using Stochastic Logical Models, Peican Zhu, Hamidreza Montazeri Aliabadi, Hasan Uludag, Jie Han 2016 Northwestern Polytechnical University

Identification Of Potential Drug Targets In Cancer Signaling Pathways Using Stochastic Logical Models, Peican Zhu, Hamidreza Montazeri Aliabadi, Hasan Uludag, Jie Han

Pharmacy Faculty Articles and Research

The investigation of vulnerable components in a signaling pathway can contribute to development of drug therapy addressing aberrations in that pathway. Here, an original signaling pathway is derived from the published literature on breast cancer models. New stochastic logical models are then developed to analyze the vulnerability of the components in multiple signalling sub-pathways involved in this signaling cascade. The computational results are consistent with the experimental results, where the selected proteins were silenced using specific siRNAs and the viability of the cells were analyzed 72 hours after silencing. The genes elF4E and NFkB are found to have nearly no ...


Understanding Dna Condensation By Low Generation (G0/G1) And Zwitterionic G4 Pamam Dendrimers, Min An 2016 University of Kentucky

Understanding Dna Condensation By Low Generation (G0/G1) And Zwitterionic G4 Pamam Dendrimers, Min An

Theses and Dissertations--Chemistry

Cationic polymers have shown potential as gene delivery vectors due to their ability to condense DNA and protect it from cellular and restriction nucleases. Dendrimers are hyperbranched macromolecules with precisely defined molecular weights and highly symmetric branches stemming from a central core. The nanosize, tunable surface chemistries and ease of surface functionalization has made dendrimers an attractive alternative to conventional linear polymers for DNA delivery applications. The commercially available, cationic dendrimer poly(amidoamine) or PAMAM is the most widely studied dendrimer for use as a gene delivery vector. The aim of this dissertation is to provide an increased understanding of ...


Human Anatomy And Physiology Preparatory Course: Part 1 Of 4 (Interactive), Carlos Liachovitzky 2016 CUNY Bronx Community College

Human Anatomy And Physiology Preparatory Course: Part 1 Of 4 (Interactive), Carlos Liachovitzky

Open Educational Resources

The overall purpose of these preparatory course set of learning objectives is to help students familiarize with some terms and some basic concepts they will find later in the Human Anatomy and Physiology I course.

These 40+ learning objectives to prepare for Human Anatomy and Physiology can be downloaded and played in a desktop, or laptop (windows exe file).

The entire course has four parts:

Each learning objective is followed by a set of multiple choice question similar to those found later in a Human Anatomy and Physiology course.

The organization and ...


Rna Nanotechnology For Next Generation Targeted Drug Delivery, Fengmei Pi 2016 University of Kentucky

Rna Nanotechnology For Next Generation Targeted Drug Delivery, Fengmei Pi

Theses and Dissertations--Pharmacy

The emerging field of RNA nanotechnology is developing into a promising platform for therapeutically application. Utilizing the state-of-art RNA nanotechnology, RNA nanoparticles can be designed and constructed with controllable shape, size for both RNA therapeutics and chemical drug delivery. The high homogeneity in particle size and ease for RNA therapeutic module conjugation, made it feasible to explore versatile RNA nanoparticle designs for preclinical studies.

One vital module for therapeutic RNA nanoparticle design is RNA aptamer, which can enable the RNA nanoparticles find its specific target for targeted drug delivery. A system of screening divalent RNA aptamers for cancer cell targeting ...


Methyl Transfer By Substrate Signaling From A Knotted Protein Fold, Thomas Christian, Reiko Sakaguchi, Agata P. Perlinska, George Lahoud, Takuhiro Ito, Erika A. Taylor, Shigeyuki Yokoyama, Joanna I. Sulkowska, Ya-Ming Hou 2015 Wesleyan University

Methyl Transfer By Substrate Signaling From A Knotted Protein Fold, Thomas Christian, Reiko Sakaguchi, Agata P. Perlinska, George Lahoud, Takuhiro Ito, Erika A. Taylor, Shigeyuki Yokoyama, Joanna I. Sulkowska, Ya-Ming Hou

Erika A. Taylor, Ph.D.

Proteins with knotted configurations, in comparison with unknotted proteins, are restricted in conformational space. Little is known regarding whether knotted proteins have sufficient dynamics to communicate between spatially separated substrate-binding sites. TrmD is a bacterial methyltransferase that uses a knotted protein fold to catalyze methyl transfer from S-adenosyl methionine (AdoMet) to G37-tRNA. The product, m1G37-tRNA, is essential for life and maintains protein-synthesis reading frames. Using an integrated approach of structural, kinetic, and computational analysis, we show that the structurally constrained TrmD knot is required for its catalytic activity. Unexpectedly, the TrmD knot undergoes complex internal movements that respond to AdoMet ...


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