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Impact Of Pooling Samples On Analytic Sensitivity Of A Real-Time Reverse Transcriptase Pcr Assay For Sars Cov-2, Subathra Marimuthu, Stephen P. Furmanek, Holly Aliesky, Leslie A. Wolf 2022 University of Louisville

Impact Of Pooling Samples On Analytic Sensitivity Of A Real-Time Reverse Transcriptase Pcr Assay For Sars Cov-2, Subathra Marimuthu, Stephen P. Furmanek, Holly Aliesky, Leslie A. Wolf

The University of Louisville Journal of Respiratory Infections

During the COVID-19 pandemic, laboratories experienced periods of shortages for certain critical materials required to meet the high demand for SARS-CoV-2 testing. The U.S. Food & Drug Administration provided a template for molecular diagnostic testing, including guidance for a specimen pooling process in order to evaluate performance of the SARS-CoV-2 nucleic acid amplification assay. This study aimed to evaluate the testing of pooled specimens consisting of four nasopharyngeal swab specimens using the Luminex ARIES® nucleic acid amplification platform. Results indicated that there was a loss of analytic sensitivity with pooled nasopharyngeal swab samples, demonstrating that this approach should be balanced ...


Platelet Micrornas Inhibit Primary Tumor Growth Via Broad Modulation Of Tumor Cell Mrna Expression In Ectopic Pancreatic Cancer In Mice, Jeremy G.T. Wurtzel, Sophia Lazar, Sonali Sikder, Kathy Q Cai, Igor Astsaturov, Andrew S Weyrich, Jesse W Rowley, Lawrence E. Goldfinger 2021 Thomas Jefferson University

Platelet Micrornas Inhibit Primary Tumor Growth Via Broad Modulation Of Tumor Cell Mrna Expression In Ectopic Pancreatic Cancer In Mice, Jeremy G.T. Wurtzel, Sophia Lazar, Sonali Sikder, Kathy Q Cai, Igor Astsaturov, Andrew S Weyrich, Jesse W Rowley, Lawrence E. Goldfinger

Department of Medicine Faculty Papers

We investigated the contributions of platelet microRNAs (miRNAs) to the rate of growth and regulation of gene expression in primary ectopic tumors using mouse models. We previously identified an inhibitory role for platelets in solid tumor growth, mediated by tumor infiltration of platelet microvesicles (microparticles) which are enriched in platelet-derived miRNAs. To investigate the specific roles of platelet miRNAs in tumor growth models, we implanted pancreatic ductal adenocarcinoma cells as a bolus into mice with megakaryocyte-/platelet-specific depletion of mature miRNAs. We observed an ~50% increase in the rate of growth of ectopic primary tumors in these mice compared to ...


Time-Resolved Cryo-Em Visualizes Ribosomal Translocation With Ef-G And Gtp, Christine E Carbone, Anna B Loveland, Howard Gamper, Ya-Ming Hou, Gabriel Demo, Andrei A Korostelev 2021 UMass Chan Medical School

Time-Resolved Cryo-Em Visualizes Ribosomal Translocation With Ef-G And Gtp, Christine E Carbone, Anna B Loveland, Howard Gamper, Ya-Ming Hou, Gabriel Demo, Andrei A Korostelev

Department of Biochemistry and Molecular Biology Faculty Papers

During translation, a conserved GTPase elongation factor-EF-G in bacteria or eEF2 in eukaryotes-translocates tRNA and mRNA through the ribosome. EF-G has been proposed to act as a flexible motor that propels tRNA and mRNA movement, as a rigid pawl that biases unidirectional translocation resulting from ribosome rearrangements, or by various combinations of motor- and pawl-like mechanisms. Using time-resolved cryo-EM, we visualized GTP-catalyzed translocation without inhibitors, capturing elusive structures of ribosome•EF-G intermediates at near-atomic resolution. Prior to translocation, EF-G binds near peptidyl-tRNA, while the rotated 30S subunit stabilizes the EF-G GTPase center. Reverse 30S rotation releases Pi and translocates peptidyl-tRNA ...


Targeting Oncogenic Gαq/11 In Uveal Melanoma, Dominic Lapadula, Jeffrey L Benovic 2021 Thomas Jefferson University

Targeting Oncogenic Gαq/11 In Uveal Melanoma, Dominic Lapadula, Jeffrey L Benovic

Department of Biochemistry and Molecular Biology Faculty Papers

Uveal melanoma is the most common intraocular cancer in adults and arises from the transformation of melanocytes in the uveal tract. While treatment of the primary tumor is often effective, 36–50% of patients develop metastatic disease primarily to the liver. While various strategies have been used to treat the metastatic disease, there remain no effective treatments that improve survival. Significant insight has been gained into the pathways that are altered in uveal melanoma, with mutually exclusive activating mutations in the GNAQ and GNA11 genes being found in over 90% of patients. These genes encode the alpha subunits of the ...


Promoter Considerations In The Design Of Lentiviral Vectors For Use In Treating Lysosomal Storage Diseases, Estera Rintz, Takashi Higuchi, Hiroshi Kobayashi, Deni S Galileo, Grzegorz Wegrzyn, Shunji Tomatsu 2021 University of Gdansk

Promoter Considerations In The Design Of Lentiviral Vectors For Use In Treating Lysosomal Storage Diseases, Estera Rintz, Takashi Higuchi, Hiroshi Kobayashi, Deni S Galileo, Grzegorz Wegrzyn, Shunji Tomatsu

Department of Pediatrics Faculty Papers

More than 50 lysosomal storage diseases (LSDs) are associated with lysosomal dysfunctions with the frequency of 1:5,000 live births. As a result of missing enzyme activity, the lysosome dysfunction accumulates undegraded or partially degraded molecules, affecting the entire body. Most of them are life-threatening diseases where patients could die within the first or second decade of life. Approximately 20 LSDs have the approved treatments, which do not provide the cure for the disorder. Therefore, the delivery of missing genes through gene therapy is a promising approach for LSDs. Over the years, ex vivo lentiviral-mediated gene therapy for LSDs ...


Tera-Seq: True End-To-End Sequencing Of Native Rna Molecules For Transcriptome Characterization, Fadia Ibrahim, Jan Oppelt, Manolis Maragkakis, Zissimos Mourelatos 2021 Thomas Jefferson University

Tera-Seq: True End-To-End Sequencing Of Native Rna Molecules For Transcriptome Characterization, Fadia Ibrahim, Jan Oppelt, Manolis Maragkakis, Zissimos Mourelatos

Department of Biochemistry and Molecular Biology Faculty Papers

Direct sequencing of single, native RNA molecules through nanopores has a strong potential to transform research in all aspects of RNA biology and clinical diagnostics. The existing platform from Oxford Nanopore Technologies is unable to sequence the very 5′ ends of RNAs and is limited to polyadenylated molecules. Here, we develop True End-to-end RNA Sequencing (TERA-Seq), a platform that addresses these limitations, permitting more thorough transcriptome characterization. TERA-Seq describes both poly-and non-polyadenylated RNA molecules and accurately identifies their native 5′ and 3′ ends by ligating uniquely designed adapters that are sequenced along with the transcript. We find that capped, full-length ...


Expression And Purification Of Phage T7 Ejection Proteins For Cryo-Em Analysis, Nicholas A. Swanson, Ravi K Lokareddy, Fenglin Li, Chun-Feng Hou, Mikhail Pavlenok, Michael Niederweis, Gino Cingolani 2021 Thomas Jefferson University

Expression And Purification Of Phage T7 Ejection Proteins For Cryo-Em Analysis, Nicholas A. Swanson, Ravi K Lokareddy, Fenglin Li, Chun-Feng Hou, Mikhail Pavlenok, Michael Niederweis, Gino Cingolani

Department of Biochemistry and Molecular Biology Faculty Papers

Bacteriophages of the Podoviridae family densely package their genomes into precursor capsids alongside internal virion proteins called ejection proteins. In phage T7 these proteins (gp14, gp15, and gp16) are ejected into the host envelope forming a DNA-ejectosome for genome delivery. Here, we describe the purification and characterization of recombinant gp14, gp15, and gp16. This protocol was used for high-resolution cryo-EM structure analysis of the T7 periplasmic tunnel and can be adapted to study ejection proteins from other phages. For complete details on the use and execution of this protocol, please refer to Swanson et al.


Inability To Switch From Arid1a-Baf To Arid1b-Baf Impairs Exit From Pluripotency And Commitment Towards Neural Crest Formation In Arid1b-Related Neurodevelopmental Disorders, Luca Pagliaroli, Patrizia Porazzi, Alyxandra T Curtis, Chiara Scopa, Harald M M Mikkers, Christian Freund, Lucia Daxinger, Sandra Deliard, Sarah A Welsh, Sarah Offley, Connor A Ott, Bruno Calabretta, Samantha A Brugmann, Gijs W E Santen, Marco Trizzino 2021 Thomas Jefferson University

Inability To Switch From Arid1a-Baf To Arid1b-Baf Impairs Exit From Pluripotency And Commitment Towards Neural Crest Formation In Arid1b-Related Neurodevelopmental Disorders, Luca Pagliaroli, Patrizia Porazzi, Alyxandra T Curtis, Chiara Scopa, Harald M M Mikkers, Christian Freund, Lucia Daxinger, Sandra Deliard, Sarah A Welsh, Sarah Offley, Connor A Ott, Bruno Calabretta, Samantha A Brugmann, Gijs W E Santen, Marco Trizzino

Department of Biochemistry and Molecular Biology Faculty Papers

Subunit switches in the BAF chromatin remodeler are essential during development. ARID1B and its paralog ARID1A encode for mutually exclusive BAF subunits. De novo ARID1B haploinsufficient mutations cause neurodevelopmental disorders, including Coffin-Siris syndrome, which is characterized by neurological and craniofacial features. Here, we leveraged ARID1B+/- Coffin-Siris patient-derived iPSCs and modeled cranial neural crest cell (CNCC) formation. We discovered that ARID1B is active only during the first stage of this process, coinciding with neuroectoderm specification, where it is part of a lineage-specific BAF configuration (ARID1B-BAF). ARID1B-BAF regulates exit from pluripotency and lineage commitment by attenuating thousands of enhancers and genes of ...


Zebrafish Paralogs Brd2a And Brd2b Are Needed For Proper Circulatory, Excretory And Central Nervous System Formation And Act As Genetic Antagonists During Development, Gregory L Branigan, Kelly S Olsen, Isabella Burda, Matthew W Haemmerle, Jason Ho, Alexandra Venuto, Nicholas D D'Antonio, Ian E Briggs, Angela J DiBenedetto 2021 University of Arizona College of Medicine-Tucson

Zebrafish Paralogs Brd2a And Brd2b Are Needed For Proper Circulatory, Excretory And Central Nervous System Formation And Act As Genetic Antagonists During Development, Gregory L Branigan, Kelly S Olsen, Isabella Burda, Matthew W Haemmerle, Jason Ho, Alexandra Venuto, Nicholas D D'Antonio, Ian E Briggs, Angela J Dibenedetto

Department of Biochemistry and Molecular Biology Faculty Papers

Brd2 belongs to the BET family of epigenetic transcriptional co-regulators that act as adaptor-scaffolds for the assembly of chromatin-modifying complexes and other factors at target gene promoters. Brd2 is a protooncogene and candidate gene for juvenile myoclonic epilepsy in humans, a homeobox gene regulator in Drosophila, and a maternal-zygotic factor and cell death modulator that is necessary for normal development of the vertebrate central nervous system (CNS). As two copies of Brd2 exist in zebrafish, we use antisense morpholino knockdown to probe the role of paralog Brd2b, as a comparative study to Brd2a, the ortholog of human Brd2. A deficiency ...


Multifunctionality Of Prostatic Acid Phosphatase In Prostate Cancer Pathogenesis, Evgenia Alpert, Armin Akhavan, Arie Gruzman, William J. Hansen, Joshua Lehrer-Graiwer, Steven C. Hall, Eric Johansen, Sean McAllister, Mittul Gulati, Ming-Fong Lin, Vishwanath R Lingappa 2021 Bioconformatics Laboratory of the California Pacific Medical Center (CPMC) Research Institute

Multifunctionality Of Prostatic Acid Phosphatase In Prostate Cancer Pathogenesis, Evgenia Alpert, Armin Akhavan, Arie Gruzman, William J. Hansen, Joshua Lehrer-Graiwer, Steven C. Hall, Eric Johansen, Sean Mcallister, Mittul Gulati, Ming-Fong Lin, Vishwanath R Lingappa

Journal Articles: Biochemistry & Molecular Biology

The role of human prostatic acid phosphatase (PAcP, P15309|PPAP_HUMAN) in prostate cancer was investigated using a new proteomics tool termed signal sequence swapping (replacement of domains from the native cleaved amino terminal signal sequence of secretory/membrane proteins with corresponding regions of functionally distinct signal sequence subtypes). This manipulation preferentially redirects proteins to different pathways of biogenesis at the endoplasmic reticulum (ER), magnifying normally difficult to detect subsets of the protein of interest. For PAcP, this technique reveals three forms identical in amino acid sequence but profoundly different in physiological functions, subcellular location, and biochemical properties. These three forms ...


Global Gene Expression Analysis Of Systemic Sclerosis Myofibroblasts Demonstrates A Marked Increase In The Expression Of Multiple Nbpf Genes, Giuseppina Abignano, Heidi Hermes, Sonsoles Piera-Velazquez, Sankar Addya, Francesco Del Galdo, Sergio A. Jimenez 2021 University of Leeds

Global Gene Expression Analysis Of Systemic Sclerosis Myofibroblasts Demonstrates A Marked Increase In The Expression Of Multiple Nbpf Genes, Giuseppina Abignano, Heidi Hermes, Sonsoles Piera-Velazquez, Sankar Addya, Francesco Del Galdo, Sergio A. Jimenez

Kimmel Cancer Center Faculty Papers

Myofibroblasts are the key effector cells responsible for the exaggerated tissue fibrosis in Systemic Sclerosis (SSc). Despite their importance to SSc pathogenesis, the specific transcriptome of SSc myofibroblasts has not been described. The purpose of this study was to identify transcriptome differences between SSc myofibroblasts and non-myofibroblastic cells. Alpha smooth muscle actin (α-SMA) expressing myofibroblasts and α-SMA negative cells were isolated employing laser capture microdissection from dermal cell cultures from four patients with diffuse SSc of recent onset. Total mRNA was extracted from both cell populations, amplified and analyzed employing microarrays. Results for specific genes were validated by Western blots ...


Cellular Origins Of Egfr-Driven Lung Cancer Cells Determine Sensitivity To Therapy, Fan Chen, Jinpeng Liu, Robert M. Flight, Kassandra J. Naughton, Alexsandr Lukyanchuk, Abigail R Edgin, Xiulong Song, Haikuo Zhang, Kwok-Kin Wong, Hunter N. B. Moseley, Chi Wang, Christine F. Brainson 2021 University of Kentucky

Cellular Origins Of Egfr-Driven Lung Cancer Cells Determine Sensitivity To Therapy, Fan Chen, Jinpeng Liu, Robert M. Flight, Kassandra J. Naughton, Alexsandr Lukyanchuk, Abigail R Edgin, Xiulong Song, Haikuo Zhang, Kwok-Kin Wong, Hunter N. B. Moseley, Chi Wang, Christine F. Brainson

Toxicology and Cancer Biology Faculty Publications

Targeting the epidermal growth factor receptor (EGFR) with tyrosine kinase inhibitors (TKIs) is one of the major precision medicine treatment options for lung adenocarcinoma. Due to common development of drug resistance to first- and second-generation TKIs, third-generation inhibitors, including osimertinib and rociletinib, have been developed. A model of EGFR-driven lung cancer and a method to develop tumors of distinct epigenetic states through 3D organotypic cultures are described here. It is discovered that activation of the EGFR T790M/L858R mutation in lung epithelial cells can drive lung cancers with alveolar or bronchiolar features, which can originate from alveolar type 2 (AT2 ...


Comparative Analysis Of Proteomics Biomarkers Associated With Residual Ridge Resorption Induced By Denture Wear, Rohana Ahmad, Ainin Sofia Mohamad Napi, Tong Wah Lim, Su Keng Tan, Saiful Anuar Karsani, Musalmah Mazlan, Lay Kek Teh, Steven M. Morgano, Nadim Z. Baba 2021 Center of Restorative Dentistry Studies, Faculty of Dentistry, Universiti Teknologi MARA, Selangor 47000, Malaysia

Comparative Analysis Of Proteomics Biomarkers Associated With Residual Ridge Resorption Induced By Denture Wear, Rohana Ahmad, Ainin Sofia Mohamad Napi, Tong Wah Lim, Su Keng Tan, Saiful Anuar Karsani, Musalmah Mazlan, Lay Kek Teh, Steven M. Morgano, Nadim Z. Baba

Makara Journal of Health Research

Background: The biochemical bone turnover markers for residual ridge resorption (RRR) are unclear. Therefore, the present study aimed to determine the biochemical bone turnover markers associated with RRR by comparing proteomics between the compressed mucosa of denture wearers and the non-compressed mucosa of non-denture wearers.

Methods: The mucosal specimens of 11 complete-denture wearers were obtained from the alveolar ridge during surgical implant exposure for implant-retained overdentures. All denture wearers had been edentulous and worn dentures for at least 5 years. The tissues of 11 non-denture wearers were taken from the ridge during minor preprosthetic surgery. The mucosal proteins were extracted ...


The Effects Of Estrogen In The Glucoregulatory Response To Exercise In Type 1 Diabetes, Mitchell James Sammut 2021 Western University

The Effects Of Estrogen In The Glucoregulatory Response To Exercise In Type 1 Diabetes, Mitchell James Sammut

Undergraduate Student Research Internships Conference

Regular exercise has shown to benefit the health of individuals with type 1 diabetes mellitus (T1DM). However, a barrier to regular exercise for this population is the fear of low blood glucose (BG) levels, also known as hypoglycemia. Hypoglycemia can result in short and long-term side-effects, such as recurring loss of consciousness or in severe cases death.

In non-diabetics, sex-related differences in fuel selection during exercise are well established. Women shift towards using fats as fuel whereas men rely mostly on sugars (i.e., carbohydrates) for energy production. Exercise during the luteal phase of the female menstrual cycle, where estrogen ...


The Penn State Protein Ladder System For Inexpensive Protein Molecular Weight Markers, Ryan T Santilli, John E Williamson, Yoshitaka Shibata, Rosalie P Sowers, Andrew N. Fleischman, Song Tan 2021 The Pennsylvania State University

The Penn State Protein Ladder System For Inexpensive Protein Molecular Weight Markers, Ryan T Santilli, John E Williamson, Yoshitaka Shibata, Rosalie P Sowers, Andrew N. Fleischman, Song Tan

Department of Anesthesiology Faculty Papers

We have created the Penn State Protein Ladder system to produce protein molecular weight markers easily and inexpensively (less than a penny a lane). The system includes plasmids which express 10, 15, 20, 30, 40, 50, 60, 80 and 100 kD proteins in E. coli. Each protein migrates appropriately on SDS-PAGE gels, is expressed at very high levels (10–50 mg per liter of culture), is easy to purify via histidine tags and can be detected directly on Western blots via engineered immunoglobulin binding domains. We have also constructed plasmids to express 150 and 250 kD proteins. For more efficient ...


Autophagy Regulation By Lipid Factors With Implications For Parkinson's Disease, Alejandro Soto-Avellaneda 2021 Boise State University

Autophagy Regulation By Lipid Factors With Implications For Parkinson's Disease, Alejandro Soto-Avellaneda

Boise State University Theses and Dissertations

Parkinson’s disease is the second most common neurodegenerative disorder. It is characterized by the death of dopaminergic neurons in the substantia nigra and a series of debilitating motor symptoms. Macroautophagy (hereafter referred to as autophagy) is a cellular process by which cells degrade proteins, lipids, organelles or dysfunctional components. Autophagy is thought to play an important role in Parkinson’s disease, because it is the only cellular process known to remove large protein aggregates, such as those seen in Parkinson’s disease pathology. Historically, a large body of work has focused on reporting on protein effectors of autophagy, and ...


Dna Polymerase Θ: A Cancer Drug Target With Reverse Transcriptase Activity, Xiaojiang Chen, Richard T. Pomerantz 2021 University of Southern California, Los Angeles

Dna Polymerase Θ: A Cancer Drug Target With Reverse Transcriptase Activity, Xiaojiang Chen, Richard T. Pomerantz

Department of Biochemistry and Molecular Biology Faculty Papers

The emergence of precision medicine from the development of Poly (ADP‐ribose) polymerase (PARP) inhibitors that preferentially kill cells defective in homologous recombination has sparked wide interest in identifying and characterizing additional DNA repair enzymes that are synthetic lethal with HR factors. DNA polymerase theta (Polθ) is a validated anti‐cancer drug target that is synthetic lethal with HR factors and other DNA repair proteins and confers cellular resistance to various genotoxic cancer therapies. Since its initial characterization as a helicase‐polymerase fusion protein in 2003, many exciting and unexpected activities of Polθ in microhomology‐mediated end‐joining (MMEJ) and ...


Characterization Of Hnrnpa1 Mutations Defines Diversity In Pathogenic Mechanisms And Clinical Presentation., Danique Beijer, Hong Joo Kim, Lin Guo, Kevin O'Donovan, Inès Mademan, Tine Deconinck, Kristof Van Schil, Charlotte M Fare, Lauren E Drake, Alice F Ford, Andrzej Kochański, Dagmara Kabzińska, Nicolas Dubuisson, Peter Van den Bergh, Nicol C Voermans, Richard Jlf Lemmers, Silvère M van der Maarel, Devon Bonner, Jacinda B Sampson, Matthew T Wheeler, Anahit Mehrabyan, Steven Palmer, Peter De Jonghe, James Shorter, J Paul Taylor, Jonathan Baets 2021 Translational Neurosciences, Faculty of Medicine and Health Sciences, and Laboratory for Neuromuscular Pathology, Institute Born-Bunge, University of Antwerp, Wilrijk, Belgium

Characterization Of Hnrnpa1 Mutations Defines Diversity In Pathogenic Mechanisms And Clinical Presentation., Danique Beijer, Hong Joo Kim, Lin Guo, Kevin O'Donovan, Inès Mademan, Tine Deconinck, Kristof Van Schil, Charlotte M Fare, Lauren E Drake, Alice F Ford, Andrzej Kochański, Dagmara Kabzińska, Nicolas Dubuisson, Peter Van Den Bergh, Nicol C Voermans, Richard Jlf Lemmers, Silvère M Van Der Maarel, Devon Bonner, Jacinda B Sampson, Matthew T Wheeler, Anahit Mehrabyan, Steven Palmer, Peter De Jonghe, James Shorter, J Paul Taylor, Jonathan Baets

Department of Biochemistry and Molecular Biology Faculty Papers

Mutations in HNRNPA1 encoding heterogeneous nuclear ribonucleoprotein (hnRNP) A1 are a rare cause of amyotrophic lateral sclerosis (ALS) and multisystem proteinopathy (MSP). hnRNPA1 is part of the group of RNA-binding proteins (RBPs) that assemble with RNA to form RNPs. hnRNPs are concentrated in the nucleus and function in pre-mRNA splicing, mRNA stability, and the regulation of transcription and translation. During stress, hnRNPs, mRNA, and other RBPs condense in the cytoplasm to form stress granules (SGs). SGs are implicated in the pathogenesis of (neuro-)degenerative diseases, including ALS and inclusion body myopathy (IBM). Mutations in RBPs that affect SG biology, including ...


Analysis Of The Dna-Binding Properties Of Alx1, An Evolutionarily Conserved Regulator Of Skeletogenesis In Echinoderms, Jennifer Guerrero-Santoro, Jian Ming Khor, Ayşe Haruka Açıkbaş, James B. Jaynes, Charles A Ettensohn 2021 Carnegie Mellon University

Analysis Of The Dna-Binding Properties Of Alx1, An Evolutionarily Conserved Regulator Of Skeletogenesis In Echinoderms, Jennifer Guerrero-Santoro, Jian Ming Khor, Ayşe Haruka Açıkbaş, James B. Jaynes, Charles A Ettensohn

Department of Biochemistry and Molecular Biology Faculty Papers

Alx1, a homeodomain-containing transcription factor, is a highly conserved regulator of skeletogenesis in echinoderms. In sea urchins, Alx1 plays a central role in the differentiation of embryonic primary mesenchyme cells (PMCs) and positively regulates the transcription of most biomineralization genes expressed by these cells. The alx1 gene arose via duplication and acquired a skeletogenic function distinct from its paralog (alx4) through the exonization of a 41-amino acid motif (the D2 domain). Alx1 and Alx4 contain glutamine-50 paired-type homeodomains, which interact preferentially with palindromic binding sites in vitro. Chromatin immunoprecipitation sequencing (ChIP-seq) studies have shown, however, that Alx1 binds both to ...


Polθ Reverse Transcribes Rna And Promotes Rna-Templated Dna Repair, Gurushankar Chandramouly, Jiemin Zhao, Shane McDevitt, Timur Rusanov, Trung Hoang, Nikita Borisonnik, Taylor Treddinick, Felicia Wednesday Lopezcolorado, Tatiana Kent, Labiba Siddique, Joseph Mallon, Jacklyn Huhn, Zainab Shoda, Ekaterina Kashkina, Alessandra Brambati, Jeremy M Stark, Xiaojiang S Chen, Richard Pomerantz 2021 Thomas Jefferson University

Polθ Reverse Transcribes Rna And Promotes Rna-Templated Dna Repair, Gurushankar Chandramouly, Jiemin Zhao, Shane Mcdevitt, Timur Rusanov, Trung Hoang, Nikita Borisonnik, Taylor Treddinick, Felicia Wednesday Lopezcolorado, Tatiana Kent, Labiba Siddique, Joseph Mallon, Jacklyn Huhn, Zainab Shoda, Ekaterina Kashkina, Alessandra Brambati, Jeremy M Stark, Xiaojiang S Chen, Richard Pomerantz

Department of Biochemistry and Molecular Biology Faculty Papers

Genome-embedded ribonucleotides arrest replicative DNA polymerases (Pols) and cause DNA breaks. Whether mammalian DNA repair Pols efficiently use template ribonucleotides and promote RNA-templated DNA repair synthesis remains unknown. We find that human Polθ reverse transcribes RNA, similar to retroviral reverse transcriptases (RTs). Polθ exhibits a significantly higher velocity and fidelity of deoxyribonucleotide incorporation on RNA versus DNA. The 3.2-Å crystal structure of Polθ on a DNA/RNA primer-template with bound deoxyribonucleotide reveals that the enzyme undergoes a major structural transformation within the thumb subdomain to accommodate A-form DNA/RNA and forms multiple hydrogen bonds with template ribose 2'-hydroxyl ...


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