A5061896814- RNA Research and Splicing
- Genomics and Chromatin Dynamics
- RNA modifications and cancer
- DNA Repair Mechanisms
- RNA and protein synthesis mechanisms
- Nuclear Structure and Function
- Ubiquitin and proteasome pathways
- Lung Cancer Research Studies
- DNA and Nucleic Acid Chemistry
- Carcinogens and Genotoxicity Assessment
- Epigenetics and DNA Methylation
- Cancer-related Molecular Pathways
- Neuroendocrine Tumor Research Advances
- Cancer-related molecular mechanisms research
- Cancer therapeutics and mechanisms
- Genetics and Neurodevelopmental Disorders
- Glycosylation and Glycoproteins Research
- Biochemical and Molecular Research
- Telomeres, Telomerase, and Senescence
- Fungal and yeast genetics research
- Endoplasmic Reticulum Stress and Disease
- Mitochondrial Function and Pathology
- Bacteriophages and microbial interactions
- Chromatin Remodeling and Cancer
- Molecular Biology Techniques and Applications
Max Planck Institute of Biophysics
2024-2025
European Molecular Biology Organization
2022-2023
UPMC Hillman Cancer Center
2014-2022
Karolinska Institutet
2016-2020
University of Cologne
2017-2019
Karolinska University Hospital
2019
University of Würzburg
2013-2018
University of Pittsburgh
2014-2016
Stockholm University
2009-2015
King's College London
2015
Significance Unrepaired DNA strand breaks at transcriptionally active sites are expected to be more deleterious than elsewhere in the genome because integrity of coding regions is likely compromised. The commonly recognized homologous recombination (HR) process occurs G2/M phase and depends on presence sister chromatids as a donor template. Our data demonstrate Cockayne syndrome protein B- RNA-dependent mechanism transcription-associated HR G0/G1 offer insight into double break repair...
Abstract Nuclear pore complexes (NPCs) constitute giant channels within the nuclear envelope that mediate nucleocytoplasmic exchange. NPC diameter is thought to be regulated by tension, but how such changes are physiologically linked cell differentiation, where mechanical properties of nuclei remodeled and mechanosensing occurs, remains unstudied. Here we used cryo-electron tomography show NPCs dilate during differentiation mouse embryonic stem cells into neural progenitors. In...
The PROSITE pattern Zinc_Finger_C2H2 was extended to permit the detection of all C2H2 zinc fingers and their parent proteins in recently completed sequence yeast genome. Additionally, a new computer program written that extracts other binding motifs (non 'fingers'), overlapping with classical finger pattern, from found set fingers. complete correct is prerequisite for classification functional terms. detected 53 do not contain clusters 10 or more repeats, as frequently higher eukaryotes....
Abstract MYC paralogs are frequently activated in small cell lung cancer (SCLC) but represent poor drug targets. Thus, a detailed mapping of -paralog-specific vulnerabilities may help to develop effective therapies for SCLC patients. Using unique cellular CRISPR activation model, we uncover that, contrast MYCN and MYCL, represses BCL2 transcription via interaction with MIZ1 DNMT3a. The resulting lack expression promotes sensitivity cycle control inhibition dependency on MCL1. Furthermore,...
Abstract Nuclear pore complexes (NPCs) mediate nucleocytoplasmic exchange, which is essential for eukaryotes. Mutations in the central scaffolding components of NPCs are associated with genetic diseases, but how they manifest only specific tissues remains unclear. This exemplified Nup133-deficient mouse embryonic stem cells, grow normally during pluripotency, differentiate poorly into neurons. Here, using an innovative situ structural biology approach, we show that Nup133 −/− cells have...
Actin and nuclear myosin 1c (NM1) cooperate in RNA polymerase I (pol I) transcription. NM1 is also part of a multiprotein assembly, B-WICH, which involved This assembly contains the chromatin remodeling complex WICH with its subunits WSTF SNF2h. We report here that binds SNF2h enhanced affinity upon impairment actin-binding function. ChIP analysis revealed NM1, SNF2h, actin gene occupancies are cell cycle-dependent require intact motor At onset division, when transcription temporarily...
The chromatin remodelling complex B-WICH, which comprises the William syndrome transcription factor (WSTF), SNF2h, and nuclear myosin 1 (NM1), is involved in regulating rDNA transcription, SiRNA silencing of WSTF leads to a reduced level 45S pre-rRNA. mechanism behind action B-WICH unclear. Here, we show that affects structure protein results compaction over 200 basepair region at rRNA promoter. knock down does not an effect on binding rRNA-specific enhancer UBF, contributes active genes....
The chaperone-related AAA ATPase Cdc48 (p97/VCP in higher eukaryotes) segregates ubiquitylated proteins for subsequent degradation by the 26S proteasome or nonproteolytic fates. specific outcome of activity is controlled evolutionary conserved cofactors Ufd2 and Ufd3, which antagonistically regulate substrates' ubiquitylation states. In contrast to interaction Ufd3 Cdc48, between ubiquitin chain elongating enzyme has not been precisely mapped. Consequently, it still unknown whether...
Kinase inhibitors represent the backbone of targeted cancer therapy, yet only a limited number oncogenic drivers are directly druggable. By interrogating activity 1,505 kinase inhibitors, we found that BRD4-NUT-rearranged NUT midline carcinoma (NMC) cells specifically killed by CDK9 inhibition (CDK9i) and depend on Cyclin-T1 expression. We show CDK9i leads to robust induction apoptosis markers DNA damage response in NMC cells. While both bromodomain over time result reduced Myc protein...
Although evidence that splicing regulates DNA repair is accumulating, the underlying mechanism(s) remain unclear. Here, we report short-term inhibition of pre-mRNA by spliceosomal inhibitors impairs cellular double-strand breaks. Indeed, interference with as little 1 h prior to irradiation reduced ubiquitylation damaged chromatin and impaired recruitment factors WRAP53β, RNF168, 53BP1, BRCA1 RAD51 sites damage. Consequently, splicing-deficient cells exhibited significant numbers residual...
Abstract Approximately half of all cases Hoyeraal–Hreidarsson syndrome (HHS), a multisystem disorder characterized by bone marrow failure, developmental defects and very short telomeres, are caused germline mutations in genes related to telomere biology. However, the varying symptoms severity disease indicate that additional mechanisms involved. Here, 3-year-old boy with HHS was found carry biallelic WRAP53 (WD40 encoding RNA antisense p53), altered two highly conserved amino acids (L283F...
Abstract The ATP‐dependent chromatin remodelling complexes SWI/SNF alter the structure in transcriptional regulation. Several classes of mammalian complex have been isolated biochemically, distinguished by a few specific subunits, such as BAF‐specific BAF250A, BAF250B and BRM, PBAF‐specific BAF180. We determined compositions using low stringency immunoprecipitation (IP) shown that pattern subunit interactions was more diverse than previously defined had predicted. association at five gene...
The ring-shaped chaperonin T-complex protein ring complex (TRiC; also known as containing TCP-1, CCT) is an ATP-driven protein-folding machine that essential for maintenance of cellular homeostasis
In eukaryotes, membrane-bound organelles create distinct molecular environments. The compartmentalizing lipid bilayer is a dynamic composite material, whose thickness and curvature modulate the structure function of membrane proteins. vitro, correlates with composition. Cellular membranes in situ, however, are continuously remodeled spatial variation their biophysical properties remains understudied. Here, we present computational approach to measure local cryo-electron tomograms. Analysis...
The conserved, ubiquitin-selective AAA ATPase Cdc48 regulates numerous cellular processes including protein quality control, DNA repair and the cell cycle. function is tightly controlled by a multitude of cofactors mediating substrate specificity processing. UBX domain Shp1 bona fide substrate-recruiting cofactor in budding yeast S. cerevisiae. Even though has been proposed to be positive regulator Glc7, catalytic subunit phosphatase 1 cerevisiae, its functions complex with remain largely...
Altered expression of the multifunctional protein WRAP53β (WD40 encoding RNA Antisense to p53), which targets repair factors DNA double-strand breaks and involved in telomere elongation Cajal bodies, is linked carcinogenesis. While loss function has been shown disrupt processes regulated by this protein, consequences its overexpression remain unclear. Here we demonstrate that disrupts formation impairs localization coilin bodies. At same time, enhanced. Following irradiation, cells...
The chromatin-remodelling complex B-WICH, comprised of William syndrome transcription factor, the ATPase SNF2h and nuclear myosin, specifically activates RNA polymerase III 5S rRNA 7SL genes. However, underlying mechanism is unknown. Using high-resolution MN walking we demonstrate here that B-WICH changes chromatin structure in vicinity genes during transcription. action required for binding machinery regulatory factors c-Myc at In addition to site genes, have revealed a novel Max intergenic...