A5081687050- RNA Research and Splicing
- RNA and protein synthesis mechanisms
- RNA modifications and cancer
- RNA regulation and disease
- Cardiomyopathy and Myosin Studies
- Circadian rhythm and melatonin
- Light effects on plants
- Mitochondrial Function and Pathology
- Thermal Regulation in Medicine
- NF-κB Signaling Pathways
- Photosynthetic Processes and Mechanisms
- Nuclear Structure and Function
- Cancer-related molecular mechanisms research
- Neurobiology and Insect Physiology Research
- CRISPR and Genetic Engineering
- Endoplasmic Reticulum Stress and Disease
- Extracellular vesicles in disease
- Neurogenetic and Muscular Disorders Research
- Genetics, Aging, and Longevity in Model Organisms
- Biosimilars and Bioanalytical Methods
- Immune Cell Function and Interaction
- Heat shock proteins research
- Viral Infections and Immunology Research
- Adipose Tissue and Metabolism
- interferon and immune responses
Freie Universität Berlin
2016-2025
Berlin Heart (Germany)
2023
Max Planck Institute for Molecular Genetics
2021
Weatherford College
2021
Laboratoire de Biochimie
2020
Justus-Liebig-Universität Gießen
2012-2014
Philipps University of Marburg
2014
Giessen School of Theology
2012
Organisms use endogenous clocks to anticipate regular environmental cycles, such as days and tides. Natural variants resulting in differently timed behaviour or physiology, known chronotypes humans, have not been well characterized at the molecular level. We sequenced genome of Clunio marinus, a marine midge whose reproduction is by circadian circalunar clocks. Midges from different locations show strain-specific genetic timing adaptations. examined variation five C. marinus strains mapped...
Alternative precursor messenger RNA splicing is instrumental in expanding the proteome of higher eukaryotes, and changes 3' splice site (3'ss) usage contribute to human disease. We demonstrate by small interfering RNA-mediated knockdowns, followed sequencing, that many proteins first recruited C* spliceosomes, which catalyze step 2 splicing, regulate alternative including selection alternatively spliced NAGNAG 3'ss. Cryo-electron microscopy protein cross-linking reveal molecular architecture...
The Brr2 helicase provides the key remodeling activity for spliceosome catalytic activation, during which it disrupts U4/U6 di-snRNP (small nuclear RNA protein), and its has to be tightly regulated. exhibits an unusual architecture, including ∼500-residue N-terminal region, whose functions molecular mechanisms are presently unknown, followed by a tandem array of structurally similar units (cassettes), only first is catalytically active. Here, we show crystal structure analysis full-length in...
CD45 encodes a trans-membrane protein-tyrosine phosphatase expressed in diverse cells of the immune system. By combinatorial use three variable exons 4–6, isoforms are generated that differ their extracellular domain, thereby modulating activity and response. Alternative splicing these involves two heterogeneous ribonucleoproteins, hnRNP L its cell-type specific paralog L-like (LL). To address complex we investigated L/LL protein expression human B-cells relation to patterns, applying...
Abstract Mammalian body temperature oscillates with the time of day and is altered in diverse pathological conditions. We recently identified a temperature‐sensitive thermometer‐like kinase, which alters SR protein phosphorylation thereby globally controls alternative splicing (AS). AS can generate unproductive variants are recognized degraded by mRNA decay pathways—including nonsense‐mediated (NMD). Here we show extensive coupling temperature‐controlled to decay, leading global control...
The fast and transient induction of immediate early genes orchestrates the cellular response to various stimuli. These stimuli trigger phosphorylation cascades that promote gene transcription independent de novo protein synthesis. Here we show same also target splicing machinery, inducing an analogous switch call (IES). We characterize hnRNPC2-controlled IES, which depends on MEK-ERK pathway T cell-specific kinase PKCθ. This mainly targets components translation such as mRNAs encoding...
Abstract The transport of secretory proteins from the endoplasmic reticulum (ER) to Golgi depends on COPII-coated vesicles. While basic principles COPII machinery have been identified, it remains largely unknown how is regulated accommodate tissue- or activation-specific differences in cargo load and identity. Here we show that activation-induced alternative splicing Sec16 controls adaptation increased upon T-cell activation. Using splice-site blocking morpholinos CRISPR/Cas9-mediated genome...
Minor and major spliceosomes control splicing of distinct intron types are thought to act largely independent one another. SR proteins essential regulators mostly connected the spliceosome. Here, we show that Srsf10 expression is controlled through an autoregulated minor intron, tightly correlating with spliceosome abundance across different tissues differentiation stages in mammals. Surprisingly, all other also correlate Srsf10, abolishing autoregulation by Crispr/Cas9-mediated deletion...
Abstract Background 3′-Untranslated regions (3′UTRs) play crucial roles in mRNA metabolism, such as by controlling stability, translation efficiency, and localization. Intriguingly, some genes the 3′UTR is longer than their coding regions, pointing to additional, unknown functions. Here, we describe a protein-coding function of 3′UTRs upon frameshift-inducing alternative splicing more 10% human mouse genes. Results 3′UTR-encoded amino acid sequences show an enrichment PxxP motifs lead...
Abstract Antiviral innate immunity represents the first defense against invading viruses and is key to control viral infections, including SARS-CoV-2. Body temperature an omnipresent variable but was neglected when addressing host mechanisms susceptibility SARS-CoV-2 infection. Here, we show that increasing in a 1.5°C window, between 36.5 38°C, strongly increases expression of genes two branches antiviral immunity, nitric oxide production type I interferon response. We alternative splicing...
The question whether interference with the ubiquitous splicing machinery can lead to cell-type specific perturbation of cellular function is addressed here by T cell ablation general U5 snRNP assembly factor CD2BP2/U5-52K. This protein defines family nuclear GYF domain containing proteins that are ubiquitously expressed in eukaryotes essential functions ascribed early embryogenesis and organ function. Abrogating CD2BP2/U5-52K cells, allows us delineate consequences interferences for...
Abstract Phosphatase and tensin homologue (PTEN) is the main antagonist of phosphatidylinositol-3-kinase (PI3K)/AKT/mTOR signalling pathway mutated in 10-20% individuals with autism spectrum disorder (ASD) exhibiting macrocephaly. Hyperactive mTOR responsible for some aspects during PTEN-ASD progression, e.g. neuronal hypertrophy -excitability, but PI3K/mTOR-independent processes have additionally been described. There emerging evidence that PTEN regulates gene transcription, spliceosome...
Abstract The intrinsically unstructured C9ORF78 protein was detected in spliceosomes but its role splicing is presently unclear. We find that tightly interacts with the spliceosome remodeling factor, BRR2, vitro. Affinity purification/mass spectrometry and RNA UV-crosslinking analyses identify additional interactors spliceosomes. Cryogenic electron microscopy structures reveal how spliceosomal B complex protein, FBP21, wrap around C-terminal helicase cassette of BRR2 a mutually exclusive...
Cell-type-specific and inducible alternative splicing has a fundamental impact on regulating gene expression cellular function in variety of settings, including activation differentiation. We have recently shown that activation-induced skipping TRAF3 exon 8 activates noncanonical NF-κB signaling upon T cell stimulation, but the regulatory basis for this event remains unknown. Here we identify cis- trans-regulatory elements rendering switch dependent type specific. The cis-acting element is...
Alternative splicing (AS) in response to changing external conditions often requires alterations the ability of sequence-specific RNA-binding proteins bind cis-acting sequences their target pre-mRNA. While daily oscillations AS events have been described several organisms, that control time day-dependent remain largely elusive. Here we define cis-regulatory RNA elements body-temperature driven rhythmic using mouse U2af26 gene as a model system. We identify complex network regulate U2af26,...
Recent work has associated point mutations in both zinc fingers (ZnF) of the spliceosome component U2AF35 with malignant transformation. However, surprisingly little is known about functionality ZnF domains general. Here we have analysed key functionalities mammalian and its paralog U2AF26. Both ZnFs are required for splicing regulation, whereas only ZnF2 controls protein stability contributes to interaction U2AF65. These features confirmed a naturally occurring splice variant U2AF26 lacking...
In eukaryotes, the removal of nuclear noncoding sequences (pre-mRNA splicing) is catalyzed by spliceosome, which consists five ribonucleoprotein particles (U1, U2, U4, U5 and U6 snRNPs, each with a respective snRNA) plethora protein factors that aid spliceosomal maturation, assembly, activation disassembly. Recently, snRNP maturation factor Aar2p from baker's yeast has been characterized structurally biochemically. binds to RNaseH (RH) Jab1/MPN domains highly conserved U5-specific Prp8p,...