A5067269795- RNA Research and Splicing
- RNA and protein synthesis mechanisms
- RNA modifications and cancer
- Nuclear Structure and Function
- Neurofibromatosis and Schwannoma Cases
- RNA regulation and disease
- Neuroblastoma Research and Treatments
- Viral Infections and Immunology Research
- Enzyme Structure and Function
- Molecular Biology Techniques and Applications
- Genetics, Aging, and Longevity in Model Organisms
- CRISPR and Genetic Engineering
- DNA Repair Mechanisms
- Cancer Research and Treatments
- Chemistry and Stereochemistry Studies
- Fungal and yeast genetics research
- RNA Interference and Gene Delivery
- Glycogen Storage Diseases and Myoclonus
- Immune Cell Function and Interaction
- Gene expression and cancer classification
- Potato Plant Research
- MicroRNA in disease regulation
- Plant nutrient uptake and metabolism
- Cellular transport and secretion
- Endoplasmic Reticulum Stress and Disease
Max Planck Institute of Biochemistry
2015-2024
Max Planck Society
2009-2020
Max Planck Institute for the Study of Societies
2020
Harvard University
2020
ETH Zurich
2020
Deutsche Forschungsgemeinschaft
2020
MRC Laboratory of Molecular Biology
2008-2018
Max Planck Institute of Psychiatry
2017
European Molecular Biology Laboratory
2003-2008
Sorbonne Université
2007
Mtr4 is a conserved RNA helicase that functions together with the nuclear exosome. It participates in processing of structured RNAs, including maturation 5.8S ribosomal (rRNA). also interacts polyadenylating Trf4-Air2 heterodimer to form so-called TRAMP ( Tr f4- A ir2- M tr4 P olyadenylation) complex. involved exosome-mediated degradation aberrant RNAs surveillance pathways. We report 2.9-Å resolution crystal structure Saccharomyces cerevisiae complex ADP and RNA. The shows central ATPase...
Nonsense-mediated mRNA decay (NMD) is a eukaryotic surveillance pathway that recognizes mRNAs with premature stop codons and targets them for rapid degradation. Evidence from previous studies has converged on UPF1 as the central NMD factor. In human cells, SMG1 kinase phosphorylates at N-terminal C-terminal tails, in turn allowing recruitment of factors SMG5, SMG6 SMG7. To understand molecular mechanisms, we recapitulated these steps vitro using purified components. We find short segment...
Messenger RNAs (mRNAs) are at the center of central dogma molecular biology. In eukaryotic cells, these long ribonucleic acid polymers do not exist as naked transcripts; rather, they associate with mRNA-binding proteins to form messenger ribonucleoprotein (mRNP) complexes. Recently, global proteomic and transcriptomic studies have provided comprehensive inventories mRNP components. However, knowledge features distinct populations has remained elusive. We purified endogenous nuclear mRNPs...
The superkiller (SKI) complex is the cytoplasmic co-factor and regulator of RNA-degrading exosome. In human cells, SKI functions mainly in co-translational surveillance-decay pathways, its malfunction linked to a severe congenital disorder, trichohepatoenteric syndrome. To obtain insights into molecular mechanisms regulating (hSKI) complex, we structurally characterized several functional states context 80S ribosomes substrate RNA. prehydrolytic ATP form, hSKI exhibits closed conformation...
In mammalian cells, spurious transcription results in a vast repertoire of unproductive non-coding RNAs, whose deleterious accumulation is prevented by rapid decay. The nuclear exosome targeting (NEXT) complex plays central role directing non-functional transcripts to exosome-mediated degradation, but the structural and molecular mechanisms remain enigmatic. Here, we elucidated architecture human NEXT complex, showing that it exists as dimer MTR4-ZCCHC8-RBM7 heterotrimers. Dimerization...
Abstract The superfamily 1B ( SF 1B) helicase Sen1 is an essential protein that plays a key role in the termination of non‐coding transcription yeast. Here, we identified ~90 kDa core Saccharomyces cerevisiae as sufficient for vitro and determined corresponding structure at 1.8 Å resolution. In addition to catalytic auxiliary subdomains characteristic family, has distinct evolutionarily conserved structural feature “braces” core. Comparative analyses indicate “brace” shaping favorable...
Highlights•Yeast Mpp6 is stably bound to the nuclear exosome core both in vivo and vitro•The middle domain binds Rrp40 subunit with conserved interactions•Mpp6 enhances ability of Mtr4 helicase channel RNA into core•The pontocerebellar W238R mutation human EXOSC3 affects hMPP6-binding siteSummaryThe RNA-degrading mediates processing decay many cellular transcripts. In yeast nucleus, ubiquitous 10-subunit complex (Exo-9–Rrp44) functions four cofactors (Rrp6, Rrp47, Mtr4, Mpp6). Biochemical...
The nuclear RNA exosome complex mediates the processing of structured RNAs and decay aberrant non-coding RNAs, an important function particularly in human cells. Most mechanistic studies to date have focused on yeast system. Here, we reconstituted studied properties a recombinant 14-subunit complex. In biochemical assays, embeds longer channel than its counterpart. 3.8 Å resolution cryo-EM structure core bound single-stranded reveals that path is formed by two distinct features hDIS3...
The RNA helicase UPF1 is a key component of the nonsense mediated mRNA decay (NMD) pathway. Previous X-ray crystal structures elucidated molecular mechanisms its catalytic activity and regulation. In this study, we examine features core identify structural element that adopts different conformations in various nucleotide- RNA-bound states UPF1. We demonstrate, using biochemical single molecule assays, modulates thereby refer to it as regulatory loop. Interestingly, there are two...
The yeast THO complex is recruited to active genes and interacts with the RNA-dependent ATPase Sub2 facilitate formation of mature export-competent messenger ribonucleoprotein particles prevent co-transcriptional RNA:DNA-hybrid-containing structures. How THO-containing complexes function at mechanistic level unclear. Here, we elucidated a 3.4 Å resolution structure Saccharomyces cerevisiae THO-Sub2 by cryo-electron microscopy. subunits Tho2 Hpr1 intertwine form platform that bound Mft1,...
PI3K-related kinases (PIKKs) are large Serine/Threonine (Ser/Thr)-protein central to the regulation of many fundamental cellular processes. PIKK family member SMG1 orchestrates progression an RNA quality control pathway, termed nonsense-mediated mRNA decay (NMD), by phosphorylating NMD factor UPF1. Phosphorylation UPF1 occurs in its unstructured N- and C-terminal regions at Serine/Threonine-Glutamine (SQ) motifs. How other PIKKs specifically recognize SQ motifs has remained unclear. Here, we...
The PI3K-related kinase (PIKK) SMG1 monitors the progression of metazoan nonsense-mediated mRNA decay (NMD) by phosphorylating RNA helicase UPF1. Previous work has shown that activity is impaired small molecule inhibitors, reduced interactors SMG8 and SMG9, downregulated so-called insertion domain. However, molecular basis for this complex regulatory network remained elusive. Here, we present cryo-electron microscopy reconstructions human SMG1-9 SMG1-8-9 complexes bound to either a inhibitor...
Abstract Nonsense-mediated mRNA decay (NMD) is a conserved co-translational surveillance and turnover pathway across eukaryotes. NMD has central role in degrading defective mRNAs also regulates the stability of significant portion transcriptome. The organized around UPF1, an RNA helicase that can interact with several NMD-specific factors. In human cells, degradation targeted begins cleavage event requires recruitment SMG6 endonuclease to UPF1. Previous studies have identified functional...