A5042093444- Cancer-related Molecular Pathways
- Gene Regulatory Network Analysis
- DNA Repair Mechanisms
- RNA Research and Splicing
- Microtubule and mitosis dynamics
- Cell Image Analysis Techniques
- Genomics and Chromatin Dynamics
- Single-cell and spatial transcriptomics
- TGF-β signaling in diseases
- Epigenetics and DNA Methylation
- Cell death mechanisms and regulation
- RNA and protein synthesis mechanisms
- Pluripotent Stem Cells Research
- Alzheimer's disease research and treatments
- Molecular Communication and Nanonetworks
- CRISPR and Genetic Engineering
- PARP inhibition in cancer therapy
- Genetics, Aging, and Longevity in Model Organisms
- Toxin Mechanisms and Immunotoxins
- NF-κB Signaling Pathways
- Cellular transport and secretion
- RNA modifications and cancer
- Genetic factors in colorectal cancer
- 3D Printing in Biomedical Research
- Advanced biosensing and bioanalysis techniques
Technical University of Darmstadt
2016-2025
Max Delbrück Center
2011-2020
Harvard University
2006-2016
Center for Systems Biology
2006-2016
Max Planck Society
2014
Max Planck Institute for Biology of Ageing
2014
Heidelberg (Poland)
2004
Heidelberg University
2004
Cells transmit information through molecular signals that often show complex dynamical patterns. The dynamic behavior of the tumor suppressor p53 varies depending on stimulus; in response to double-strand DNA breaks, it shows a series repeated pulses. Using computational model, we identified sequence precisely timed drug additions alter pulses instead produce sustained response. This leads expression different set downstream genes and also alters cell fate: experience recover from damage,...
Mitotic arrest induced by antimitotic drugs can cause apoptosis or p53-dependent cell cycle arrest. It also DNA damage, but the relationship between these events has been unclear. Live, single-cell imaging in human cancer cells responding to an kinesin-5 inhibitor and additional revealed strong induction of p53 after slipped from prolonged mitotic into G1. We investigated this induction. detected damage late slippage. This was inhibited treatment with caspase inhibitors stable expression...
Peptides are promising drug modalities that can modulate protein–protein interactions, but their application is hampered by limited ability to reach intracellular targets. Here, we improved the cytosolic delivery of a peptide blocking p53:MDM2/X interactions using cyclotide as stabilizing scaffold. We applied several design strategies improve and found conjugation lead cyclic cell-penetrating cR10 was most effective. Conjugation allowed cell internalization at micromolar concentration led...
In response to DNA damage, cells arrest at specific stages in the cell cycle. This must fulfill least 3 requirements: it be activated promptly; sustained as long damage is present prevent loss of genomic information; and after arrest, re-enter into appropriate cycle phase ensure proper ploidy. Multiple molecular mechanisms capable arresting have been identified mammalian cells; however, unknown whether each mechanism meets all requirements or they act together confer functions arrest. To...
Abstract Background RNA-binding proteins (RBPs) mediate mRNA biogenesis, translation and decay. We recently developed an approach to profile transcriptome-wide RBP contacts on polyadenylated transcripts by next-generation sequencing. A comparison of such profiles from different biological conditions has the power unravel dynamic changes in protein-contacted cis -regulatory regions without a priori knowledge regulatory protein component. Results compared occupancy MCF7 HEK293 cells. Briefly,...
The tumor suppressor protein p53 is activated by cellular stress. DNA double strand breaks (DSBs) induce the activation of kinase ATM, which stabilizes and activates its transcriptional activity. Single cell analysis revealed that DSBs induced gamma irradiation trigger accumulation in a series pulses vary number from to cell. Higher levels increase suggesting they arise periodic examination damage ATM. If persists, additional are triggered. threshold required for activating pulse unclear....
Abstract Chlamydia , a major human bacterial pathogen, assumes effective strategies to protect infected cells against death-inducing stimuli, thereby ensuring completion of its developmental cycle. Paired with capacity cause extensive host DNA damage, this poses potential risk malignant transformation, consistent circumstantial epidemiological evidence. Here we reveal dramatic depletion p53, tumor suppressor deregulated in many cancers, during infection. Using biochemical approaches and live...
Article25 January 2018Open Access Transparent process Cell-specific responses to the cytokine TGFβ are determined by variability in protein levels Jette Strasen Berlin Institute for Medical Systems Biology, Max Delbrueck Center Helmholtz Association, Berlin, Germany Search more papers this author Uddipan Sarma of Molecular Biology (IMB), Mainz, Marcel Jentsch Department Technische Universität Darmstadt, Stefan Bohn Caibin Sheng Daniel Horbelt Chemistry and Biochemistry, Freie Petra Knaus...
A functional DNA damage response is essential for maintaining genome integrity in the presence of double-strand breaks. It mainly coordinated by kinases ATM, ATR, and DNA-PKcs, which control repair broken strands relay signal to tumor suppressor p53 induce cell cycle arrest, apoptosis, or senescence. Although many functions individual have been identified, it remains unclear how they act concert ensure faithful processing signal. Using specific inhibitors quantitative analysis at single-cell...
Abstract Convergent transcription, that is, the collision of sense and antisense is ubiquitous in mammalian genomes believed to diminish RNA expression. Recently, transcription downstream promoters was found be surprisingly prevalent. However, functional characteristics affected are poorly investigated. Here we show convergent marks an unexpected positively co-regulated promoter constellation. By assessing transcriptional dynamic systems, identified constituent connected through a distinct...
Recent studies have shown that many cell-signaling networks contain interactions and feedback loops give rise to complex dynamics. Synthetic biology has allowed researchers construct analyze well-defined signaling circuits exhibiting behavior can be predicted quantitatively understood. Combining these approaches—wiring natural network components together with engineered interactions—has the potential precisely modulate dynamics of endogenous processes control cell decisions they influence....
Abstract Cellular signaling systems precisely transmit information in the presence of molecular noise while retaining flexibility to accommodate needs individual cells. To understand design principles underlying such versatile signaling, we analyzed response tumor suppressor p53 varying levels DNA damage hundreds cells and observed a switch between distinct modes characterized by isolated pulses sustained oscillations accumulation. Guided dynamic theory show that this requires an excitable...
Discontinuous transcription has been described for different mammalian cell lines and numerous promoters. However, our knowledge of how the activity individual promoters is adjusted by dynamic signaling inputs from factors limited. To address this question, we characterized selected target genes that are regulated pulsatile accumulation tumor suppressor p53 in response to ionizing radiation. We performed time-resolved measurements gene expression at single-cell level smFISH used resulting...
To enable reliable cell fate decisions, mammalian cells need to adjust their responses dynamically changing internal states by rewiring the corresponding signaling networks. Here, we combine time-lapse microscopy of endogenous fluorescent reporters with computational analysis understand at single-cell level how p53-mediated DNA damage response is adjusted during cycle progression. Shape-based clustering revealed that dynamics CDK inhibitor p21 diverges from its transcription factor p53 S...