A5069799043- RNA modifications and cancer
- RNA and protein synthesis mechanisms
- RNA Research and Splicing
- Peptidase Inhibition and Analysis
- Antifungal resistance and susceptibility
- Fungal Infections and Studies
- Cancer-related gene regulation
- Enzyme Structure and Function
- Molecular Biology Techniques and Applications
- Cancer-related molecular mechanisms research
- Mentoring and Academic Development
- DNA Repair Mechanisms
- Pneumocystis jirovecii pneumonia detection and treatment
- TGF-β signaling in diseases
- Bacteriophages and microbial interactions
- Advanced biosensing and bioanalysis techniques
- Immune cells in cancer
- Career Development and Diversity
- Health and Medical Research Impacts
- Cancer Cells and Metastasis
- Bacterial Genetics and Biotechnology
Emory University
2019-2025
Scripps Research Institute
2015-2020
Max Planck Institute for Biophysical Chemistry
2010-2014
Freie Universität Berlin
2010-2014
SignificanceThe presence of RNA chemical modifications has long been known, but their precise molecular consequences remain unknown. 2'-O-methylation is an abundant modification that exists in all domains life. Ribosomal (rRNA) represents a functionally important heavily modified by 2'-O-methylations. Although at regions the rRNA, contribution 2'-O-methylations to ribosome activities By establishing method disturb rRNA patterns, we show affect function and fidelity change balance between...
Casein kinase 1δ/ε (CK1δ/ε) and their yeast homologue Hrr25 are essential for cell growth. Further, CK1δ is overexpressed in several malignancies, inhibitors have shown promise preclinical animal studies. However, the substrates of CK1δ/ε that necessary growth survival unknown. We show ribosome assembly, where it phosphorylates assembly factor Ltv1, which causes its release from nascent 40S subunits allows subunit maturation. inactivation or expression a nonphosphorylatable Ltv1 variant...
The RNA exosome is a ribonuclease complex that mediates both processing and degradation. This evolutionarily conserved, ubiquitously expressed, required for fundamental cellular functions, including rRNA processing. plays roles in regulating gene expression protecting the genome, modulating accumulation of RNA-DNA hybrids (R-loops). function facilitated by cofactors, such as helicase MTR4, which binds/remodels RNAs. Recently, missense mutations subunit genes have been linked to neurological...
The correct assembly of ribosomes from ribosomal RNAs (rRNAs) and proteins (RPs) is critical, as indicated by the diseases caused RP haploinsufficiency loss stoichiometry in cancer cells. Nevertheless, how each ensured remains poorly understood. We use yeast genetics, biochemistry, structure probing to show that factor Ltv1 facilitates incorporation Rps3, Rps10, Asc1/RACK1 into small subunit head. Ribosomes Ltv1-deficient have substoichiometric amounts Rps10 Asc1 defects translational...
Premature release of nascent ribosomes into the translating pool must be prevented because these do not support viability and may prone to mistakes. Here, we show that kinase Rio1, nuclease Nob1, its binding partner Pno1 cooperate establish a checkpoint prevents escape immature polysomes. Nob1 blocks mRNA recruitment, rRNA cleavage is required for dissociation from 40S subunits, thereby setting up maturation. Rio1 releases pre-40S discharge pool. Weak-binding mutants can bypass requirement...
During translation initiation, 40S ribosomes scan the mRNA until they encounter start codon, where conformational changes produce a translation-competent 80S complex. Destabilizing scanning complex results in misinitiation at non-AUG codons, demonstrating its importance for fidelity. Here, we use combination of biochemical and genetic analyses to demonstrate that ability nascent subunit adopt is tested during assembly via structural mimicry. Specifically, formation 80S-like intermediate,...
The RNA exosome is a multi-subunit, evolutionarily conserved ribonuclease complex that essential for processing, decay and surveillance of many cellular RNAs. Missense mutations in genes encoding the structural subunits cause diverse range diseases, collectively known as exosomopathies, often involving neurological developmental defects. varied symptoms suggest different lead to distinct vivo consequences. To investigate these functional consequences distinguish whether they are unique each...
During their maturation, nascent 40S subunits enter a translation-like quality control cycle, where they are joined by mature 60S to form 80S-like ribosomes. While these assembly intermediates essential for maturation and control, how form, structure promotes remains unknown. To address questions, we determined the of an ribosome intermediate overall resolution 3.4 Å. The structure, validated biochemical data, resolves large body previously paradoxical data illustrates translation factors...
Posttranslational modifications (PTMs) such as phosphorylation of RNA-binding proteins (RBPs) regulate several critical steps in RNA metabolism, including spliceosome assembly, alternative splicing, and mRNA export. Notably, serine-/arginine- (SR)-rich RBPs are densely phosphorylated compared with the remainder proteome. Previously, we showed that dephosphorylation splicing factor SRSF2 regulated increased interactions similar arginine-rich U1-70K LUC7L3. However, large-scale functional...
The RNA exosome is an evolutionarily conserved complex required for both precise processing and decay. Pathogenic variants in EXOSC genes, which encode structural subunits of this complex, are linked to several autosomal recessive disorders. Here, we describe a missense allele the EXOSC4 gene that causes collection clinical features two affected siblings. This variant (NM_019037.3: exon3:c.560T>C) changes leucine residue within region proline (p.Leu187Pro). individuals show prenatal growth...
Human proteins 15.5K and hPrp31 are components of the major spliceosomal U4 snRNP minor U4atac snRNP. The two bind to related 5′-stem loops (5′SLs) snRNAs in a strictly sequential fashion. primary binding protein binds at K-turns that exhibit identical sequences snRNAs. However, RNA contacted by secondary differ snRNAs, mechanism which achieves its dual specificity is presently unknown. We show crystal structure analysis capping pentaloops 5′SLs adopt different structures ternary...
Archaeal and eukaryotic box C/D RNPs catalyze the 2′- O -methylation of ribosomal RNA, a modification that is essential for correct folding function ribosome. Each archaeal RNP contains three core proteins—L7Ae, Nop5, fibrillarin (methyltransferase)—and sRNA. Base-pairing between sRNA guide region rRNA directs target site selection with related C′/D′ motifs functioning as protein binding sites. Recent structural analysis in vitro assembled complexes has produced two divergent models sRNP...
Instead of a classical single-stranded deoxyribonuleic acid (DNA)-binding protein (SSB), some hyperthermophilic crenarchaea harbor non-canonical SSB termed ThermoDBP. Two related but poorly characterized groups proteins, which share the ThermoDBP N-terminal DNA-binding domain, have broader phylogenetic distribution and co-exist with ThermoDBPs and/or other SSBs. We investigated nucleic binding properties crystal structures representatives these ThermoDBP-related proteins (ThermoDBP-RPs) 1 2....
Regulation of protein synthesis is critical for control gene expression in all cells. Ribosomes are ribonucleoprotein machines responsible translating cellular proteins. Defects ribosome production, function, or regulation detrimental to the cell and cause human diseases, such as progressive encephalopathy with edema, hypsarrhythmia, optic atrophy (PEHO) syndrome. PEHO syndrome a devastating neurodevelopmental disorder caused by mutations ZNHIT3 gene, which encodes an evolutionarily...
The RNA exosome is an evolutionarily conserved exoribonuclease complex that consists of a 3-subunit cap, 6-subunit barrel-shaped core, and catalytic base subunit. Missense mutations in genes encoding structural subunits the cause growing family diseases with diverse pathologies, collectively termed exosomopathies. disease symptoms vary can manifest as neurological defects or developmental disorders. diversity exosomopathy pathologies suggests different missense result distinct vivo...
Abstract The RNA exosome is a ribonuclease complex that mediates both processing and degradation. This evolutionarily conserved, ubiquitously expressed, required for fundamental cellular functions, including rRNA processing. plays roles in regulating gene expression protecting the genome, modulating accumulation of RNA-DNA hybrids (R-loops). function facilitated by cofactors, such as helicase MTR4, which binds/remodels RNAs. Recently, missense mutations subunit genes have been linked to...
In 2020, the American Society of Biochemistry and Molecular Biology (ASBMB) Women in Committee introduced ASBMB Leadership Awards to recognize individuals with a strong commitment advancing careers women biochemistry molecular biology along demonstrated excellence research, discovery, and/or service. This innovative award recognizes efforts mentor support trainees colleagues at all levels. Such leadership provides opportunity focus briefly on important role mentoring within STEM disciplines....