A5054277797- RNA and protein synthesis mechanisms
- RNA modifications and cancer
- RNA Research and Splicing
- Cystic Fibrosis Research Advances
- Advanced biosensing and bioanalysis techniques
- Lysosomal Storage Disorders Research
- CRISPR and Genetic Engineering
- Enzyme Structure and Function
- Carbohydrate Chemistry and Synthesis
- Neonatal Respiratory Health Research
- Respiratory viral infections research
- Bacterial Genetics and Biotechnology
- Neurogenetic and Muscular Disorders Research
- Cellular transport and secretion
- Fungal and yeast genetics research
- Glycosylation and Glycoproteins Research
- Peptidase Inhibition and Analysis
- Neurofibromatosis and Schwannoma Cases
- Virus-based gene therapy research
- Genomics, phytochemicals, and oxidative stress
- Genomics and Phylogenetic Studies
- Wnt/β-catenin signaling in development and cancer
- Biochemical and Molecular Research
- Connective tissue disorders research
- Genetics and Neurodevelopmental Disorders
University of Alabama at Birmingham
2013-2024
University of Alabama
2012-2023
Case Western Reserve University
2023
Pediatrics and Genetics
2023
Cystic Fibrosis Foundation
2017
Czech Academy of Sciences, Institute of Microbiology
2011-2016
Marshall Space Flight Center
1994-1999
New Century Pharmaceuticals (United States)
1999
National Aeronautics and Space Administration
1994
Significance The drug ataluren restores activity to otherwise nonfunctional nonsense alleles, a capability possibly reflecting the insertion of near-cognate aminoacyl tRNAs at premature termination codons during protein synthesis. Because alleles comprise significant fraction all causing inherited disorders, drugs that promote such codon readthrough have broad therapeutic potential. However, effectiveness suppression depends on nature amino acids inserted each three codons. Here we...
The translation machinery recognizes codons that enter the ribosomal A site with remarkable accuracy to ensure polypeptide synthesis proceeds a minimum of errors. When termination codon enters eukaryotic ribosome, it is recognized by release factor eRF1. It has been suggested recognition signals in these organisms not limited simple trinucleotide codon, but instead an extended tetranucleotide signal comprised stop and first nucleotide follows. Interestingly, pharmacological agents such as...
Several crystal forms of serum albumin suitable for three‐dimensional structure determination have been grown. These include crystals recombinant and wild‐type human albumin, baboon canine albumin. The intrinsic limits X‐ray diffraction these are in the range 0.28–0.22 nm. Two produced from incorporated long‐chain fatty acids. Molecular replacement experiments successfully conducted on each form using previously determined atomic coordinates illustrating conserved tertiary structure.
Nonsense suppression therapy is an approach to treat genetic diseases caused by nonsense mutations. This therapeutic strategy pharmacologically suppresses translation termination at Premature Termination Codons (PTCs) in order restore expression of functional protein. However, the process Nonsense-Mediated mRNA Decay (NMD), which reduces abundance mRNAs containing PTCs, frequently limits this approach. Here, we used a mouse model lysosomal storage disease mucopolysaccharidosis I-Hurler (MPS...
Abstract Premature termination codons (PTCs) prevent translation of a full-length protein and trigger nonsense-mediated mRNA decay (NMD). Nonsense suppression (also termed readthrough) therapy restores function by selectively suppressing at PTCs. Poor efficacy current readthrough agents prompted us to search for better compounds. An NMD-sensitive NanoLuc reporter was used screen 771,345 Among the 180 compounds identified with activity, SRI-37240 its more potent derivative SRI-41315, induce...
Abstract Protein synthesis terminates when a stop codon enters the ribosome’s A-site. Although termination is efficient, readthrough can occur near-cognate tRNA outcompetes release factors during decoding. Seeking to understand regulation we used machine learning approach analyze efficiency data from published HEK293T ribosome profiling experiments and compared it comparable yeast experiments. We obtained evidence for conservation of identities codon, its context, 3’-UTR length (when...
The Nonsense-Mediated mRNA Decay (NMD) pathway mediates the rapid degradation of mRNAs that contain premature stop mutations in eukaryotic organisms. It was recently shown three yeast genes encode proteins involved NMD process, UPF1, UPF2, and UPF3, also reduce efficiency translation termination. In current study, we compared termination a upf1Delta strain [PSI(+)] using collection reporter constructs. state is caused by prion form polypeptide chain release factor eRF3 limits its...
Hurler syndrome is the most severe form of a lysosomal storage disease caused by loss enzyme α-l-iduronidase (encoded IDUA gene), which participates in degradation glycosaminoglycans (GAGs) within lysosome. In some populations, premature stop mutations represent roughly two-thirds that cause syndrome. this study we investigated whether aminoglycoside gentamicin can suppress gene. We found fibroblast cell line heterozygous for Q70X and W402X showed significant increase activity when cultured...
Abstract The 3‐dimensional crystal structure of glutathione S ‐transferase (GST) Schistosoma japonicum (Sj) fused with a conserved neutralizing epitope on gp41 (glycoprotein, 41 kDa) human immunodeficiency virus type 1 (HIV‐1) (Muster T et al., 1993, J Virol 67 :6642–6647) was determined at 2.5 Å resolution. the 3‐3 isozyme rat GST μ gene class (Ji X, Zhang P, Armstrong RN, Gilliland GL, 1992, Biochemistry 31 :10169–10184) used as molecular replacement model. consists 4‐stranded β‐sheet and...
In-frame premature termination codons (PTCs) account for ∼11% of all disease-associated mutations. PTC suppression therapy utilizes small molecules that suppress translation at a to restore synthesis full-length protein. is mediated by the base pairing near-cognate aminoacyl-tRNA with and subsequently, amino acid becomes incorporated into nascent polypeptide site PTC. However, little known about identity acid(s) inserted during this process in mammalian cells, or how surrounding sequence...
Rationale: Premature termination codons (PTCs) in the cystic fibrosis transmembrane conductance regulator (CFTR) gene cause (CF). Several agents are known to suppress PTCs but poorly efficacious or toxic.Objectives: To determine whether there clinically available that elicit translational readthrough and improve CFTR function sufficient confer therapeutic benefit patients with CF PTCs.Methods: Two independent screens, firefly luciferase CFTR-mediated transepithelial chloride assay, were...
We sought to establish whether the cystic fibrosis transmembrane conductance regulator (CFTR) regulates activity of amiloride-sensitive sodium channels (ENaC) in alveolar epithelial cells wild-type, heterozygous ( Cftr +/− ), knockout −/− and ΔF508-expressing mice situ. RT-PCR studies confirmed presence CFTR message freshly isolated type II (ATII) from wild-type mice. patched I (ATI) ATII prepared lung slices these demonstrated 4-pS ENaC with following basal open probabilities (P o ):...
AbstractIn this report, we show that the Saccharomyces cerevisiae protein Tpa1p (for termination and polyadenylation) influences translation efficiency, mRNA poly(A) tail length, stability. is encoded by previously uncharacterized open reading frame YER049W. Yeast strains carrying a deletion of TPA1 gene (tpa1Δ) exhibited increased readthrough stop codons, coimmunoprecipitation assays revealed interacts with factors eRF1 eRF3. In addition, tpa1Δ mutation led to 1.5- 2-fold increase in...