A5064674592- RNA and protein synthesis mechanisms
- RNA modifications and cancer
- RNA Research and Splicing
- Cancer-related gene regulation
- Microtubule and mitosis dynamics
- Reproductive Biology and Fertility
- Molecular Biology Techniques and Applications
- Genomics and Chromatin Dynamics
- Epigenetics and DNA Methylation
- Genetics, Aging, and Longevity in Model Organisms
- Heat shock proteins research
- Erythrocyte Function and Pathophysiology
- Sperm and Testicular Function
- Cellular transport and secretion
- Nuclear Structure and Function
- Cytomegalovirus and herpesvirus research
- Physiological and biochemical adaptations
- Prenatal Screening and Diagnostics
- Mitochondrial Function and Pathology
- Renal and related cancers
- Mechanisms of cancer metastasis
- Circadian rhythm and melatonin
- RNA Interference and Gene Delivery
- Spaceflight effects on biology
- Genomics and Phylogenetic Studies
University of Göttingen
2023-2025
Universitätsmedizin Göttingen
2023-2025
Max Planck Institute for Multidisciplinary Sciences
2022-2024
Bioanalytica (Switzerland)
2024
City University of New York
2024
Max Planck Institute for the Study of Religious and Ethnic Diversity
2024
Bourn Hall Clinic
2023
Max Planck Institute for Biophysical Chemistry
2018-2021
Heidelberg University
2021
Full-grown oocytes are transcriptionally silent and must stably maintain the messenger RNAs (mRNAs) needed for oocyte meiotic maturation early embryonic development. However, where how mammalian store maternal mRNAs is unclear. Here, we report that accumulate in a mitochondria-associated ribonucleoprotein domain (MARDO). MARDO assembly around mitochondria was promoted by RNA-binding protein ZAR1 directed an increase mitochondrial membrane potential during growth. foci coalesced into...
Mammalian oocytes are filled with poorly understood structures called cytoplasmic lattices. First discovered in the 1960s and speculated to correspond mammalian yolk, ribosomal arrays, or intermediate filaments, their function has remained enigmatic date. Here, we show that lattices sites where store essential proteins for early embryonic development. Using super-resolution light microscopy cryoelectron tomography, composed of filaments a high surface area, which contain PADI6 subcortical...
Abstract The mechanisms by which viruses hijack the genetic machinery of cells they infect are current interest. When bacteriophage T4 infects Escherichia coli , it uses three different adenosine diphosphate (ADP)-ribosyltransferases (ARTs) to reprogram transcriptional and translational apparatus host ADP-ribosylation using nicotinamide adenine dinucleotide (NAD) as a substrate 1,2 . NAD has previously been identified 5′ modification cellular RNAs 3–5 Here we report that ART ModB accepts not...
The reaction of CO2 with H2O to form bicarbonate (HCO3-) and H+ controls sperm motility fertilization via HCO3--stimulated cAMP synthesis. A complex network signaling proteins participates in this reaction. Here, we identify key players that regulate intracellular pH (pHi) HCO3- human by quantitative mass spectrometry (MS) kinetic patch-clamp fluorometry. resting pHi is set amiloride-sensitive Na+/H+ exchange. sperm-specific putative exchanger SLC9C1, unlike its sea urchin homologue, not...
Abstract Women are born with all of their oocytes. The oocyte proteome must be maintained minimal damage throughout the woman’s reproductive life, and hence for decades. Here we report that ovarian proteostasis involves extreme protein longevity. Mouse ovaries had more extremely long-lived proteins than other tissues, including brain. These diverse functions, in mitochondria, cytoskeleton, chromatin proteostasis. stable resided not only oocytes but also somatic cells. Our data suggest...
Abstract Mitochondria contain dedicated ribosomes (mitoribosomes), which synthesize the mitochondrial-encoded core components of oxidative phosphorylation complexes. The RNA and protein mitoribosomes are encoded on two different genomes (mitochondrial nuclear) assembled into functional complexes with help factors inside organelle. Defects in mitoribosome biogenesis associated severe human diseases, yet molecular pathway assembly remains poorly understood. Here, we applied a multidisciplinary...
The pentameric FERRY Rab5 effector complex is a molecular link between mRNA and early endosomes in intracellular distribution. Here, we determine the cryo-EM structure of human FERRY. It reveals unique clamp-like architecture that bears no resemblance to any known Rab effectors. A combination functional mutational studies while Fy-2 C-terminal coiled-coil acts as binding region for Fy-1/3 Rab5, both coiled-coils Fy-5 concur bind mRNA. Mutations causing truncations patients with neurological...
Abstract Protein–DNA interactions are key to the functionality and stability of genome. Identification mapping protein–DNA interaction interfaces sites is crucial for understanding DNA-dependent processes. Here, we present a workflow that allows mass spectrometric (MS) identification proteins in direct contact with DNA reconstituted native chromatin after cross-linking by ultraviolet (UV) light. Our approach enables determination at amino-acid level. With example chromatin-associated protein...
5-Methyluridine (m5U) is one of the most abundant RNA modifications found in cytosolic tRNA. tRNA methyltransferase 2 homolog A (hTRMT2A) dedicated mammalian enzyme for m5U formation at position 54. However, its binding specificity and functional role cell are not well understood. Here we dissected structural sequence requirements methylation targets. Specificity modification by hTRMT2A achieved a combination modest preference presence uridine 54 tRNAs. Mutational analysis together with...
Abstract Polo-like kinase 1 (PLK1) is a conserved regulator of cell division. During mitotic prophase, PLK1 contributes to the activation cyclin-dependent (CDK1). However, exact functions in prophase remain incompletely understood. Here, we show that inhibition synchronous G2 populations multiple mammalian lines delays or prevents entry with high variability between individual cells. Using mathematical model, recapitulate this phenomenon and provide an explanation for observed phenotypic...
Dnmt2 methylates cytosine at position 38 of tRNAAsp in a variety eukaryotic organisms. A correlation between the presence hypermodified nucleoside queuosine (Q) 34 and dependent C38 methylation was recently found vivo for S. pombe D. discoideum. We demonstrate direct effect Q-modification on methyltransferase catalytic efficiency vitro, as Vmax/K0.5 purified shows an increase vitro transcribed containing Q34 to 6.27 ∗ 10-3 s-1 µM-1 compared 1.51 unmodified substrate. Q34tRNAAsp exhibits only...
The eukaryotic tRNA guanine transglycosylase (TGT) is an RNA modifying enzyme incorporating queuine, a hypermodified derivative, into the tRNAsAsp,Asn,His,Tyr. While both subunits of functional heterodimer have been crystallized individually, much our understanding its dimer interface or recognition target has inferred from more thoroughly studied bacterial homolog. However, since TGT, by queuine precursor preQ1, deviates not only in function, but as homodimer, also subunit architecture, any...
In protein-RNA cross-linking mass spectrometry, UV or chemical introduces stable bonds between amino acids and nucleic in complexes that are then analyzed detected spectra. This analytical tool delivers valuable information about RNA-protein interactions RNA docking sites proteins, both vitro vivo. The identification of cross-linked peptides with oligonucleotides different length leads to a combinatorial increase search space. We demonstrate the peptide retention time prediction tasks can be...
ABSTRACT UV (ultra-violet) crosslinking with mass spectrometry (XL-MS) has been established for identifying RNA-and DNA-binding proteins along their domains and amino acids involved. Here, we explore chemical XL-MS RNA-protein, DNA-protein, nucleotide-protein complexes in vitro vivo . We introduce a specialized nucleotide-protein-crosslink search engine, NuXL, robust fast identification of such crosslinks at acid resolution. Chemical complements by generating different crosslink species,...
TrmB belongs to the class I S-adenosylmethionine (SAM)-dependent methyltransferases (MTases) and introduces a methyl group guanine at position 7 (m7G) in tRNA. In tRNAs m7G is most frequently found 46 variable loop forms tertiary base pair with C13 U22, introducing positive charge G46. The TrmB/Trm8 enzyme family structurally diverse, as proteins exist monomeric, homodimeric, heterodimeric form. So far, exact enzymatic mechanism, well tRNA-TrmB crystal structure not known. Here we present...
Abstract Regulation of RNA helicase activity, often accomplished by protein cofactors, is essential to ensure target specificity within the complex cellular environment. The largest family cofactors are G-patch proteins, but cognate helicases and functions numerous human proteins remain elusive. Here, we discover that GPATCH4 a stimulatory cofactor DHX15 interacts with DEAH box in nucleolus via residues its domain. We reveal associates pre-ribosomal particles, crosslinks transcribed...
Abstract Long-range mRNA transport is crucial for the spatio-temporal regulation of gene expression, and its malfunction leads to neurological disorders. The pentameric FERRY Rab5 effector complex molecular link between early endosomes in intracellular distribution. Here, we determine cryo-EM structure human complex, composed Fy-1 Fy-5. reveals a clamp-like architecture, where two arm-like appendages Fy-2 Fy-5 dimer, protrude from central Fy-4 dimer. coiled-coil domains are flexible project...
Abstract The Mos kinase is a constitutive activator of the ERK/MAPK pathway exclusively expressed during oocyte meiosis, mediating key meiotic functions across animal species. While few its downstream effectors have been studied in some detail, molecular targets under control Mos-MAPK not yet identified systematically. Here, we combined live-cell microscopy starfish oocytes to characterize cellular phenotypes caused by inhibition with phosphoproteomic analysis synchronous populations at...
Abstract Polo-like kinase 1 (plk1) is a conserved regulator of cell division. During prophase, plk1 phosphorylates direct substrates and involved in activation the cyclin-dependent (cdk1). However, exact functions prophase remain incompletely understood. By testing several lines small-molecule inhibitors, we confirm that inhibition causes delay mitotic entry. We show cells are delayed prophase-like state displaying progressively condensing chromosomes, increased microtubule dynamics,...
Abstract The eukaryotic microrchidia (MORC) protein family are DNA g yrase, H sp90, histidine k inase, Mut L (GHKL)-type ATPases involved in gene expression regulation and chromatin compaction. molecular mechanisms underlying these activities incompletely understood. Here we studied the full-length human MORC2 biochemically. We identified a binding site C-terminus of protein, observe that this region is heavily phosphorylated cells. Phosphorylation reduces its affinity for appears to exclude...
Abstract The eukaryotic microrchidia (MORC) protein family are DNA gyrase, Hsp90, histidine kinase, MutL (GHKL)-type ATPases involved in gene expression regulation and chromatin compaction. molecular mechanisms underlying these activities incompletely understood. Here, we studied the full-length human MORC2 biochemically. We identified a binding site C-terminus of protein, observe that this region can be phosphorylated cells. by reduces its ATPase activity entrap multiple substrates between...
The mechanisms by which viruses hijack their host’s genetic machinery are of current interest. When bacteriophage T4 infects Escherichia coli , three different ARTs (ADP-ribosyltransferases) reprogram the transcriptional and translational apparatus through ADP-ribosylation using nicotinamide adenine dinucleotide (NAD) as substrate 1,2 . Recently, NAD was identified a 5’-modification cellular RNAs 3–5 Here, we report that ART ModB accepts not only but also NAD-capped RNA (NAD-RNA) attaches...
To protect genome integrity, cells have acquired defense mechanisms against invasive genetic material, such as retroelements that integrate into host genomes. The ATPase MORC2 (Microrchidia family CW-type zing finger 2) is critical for the transcriptional silencing of in human genome. Loss known to increase expression LINE-1 retrotransposon and integrated proviral DNA from retrovirus HIV-1. hypothesized contribute by limiting accessibility through compaction; however, molecular mechanism...