A5036336178- DNA Repair Mechanisms
- CRISPR and Genetic Engineering
- Cancer-related Molecular Pathways
- Cancer Genomics and Diagnostics
- Genetic factors in colorectal cancer
- Cancer therapeutics and mechanisms
- PARP inhibition in cancer therapy
- Genomics and Chromatin Dynamics
- Immunodeficiency and Autoimmune Disorders
- Immune Cell Function and Interaction
- Pluripotent Stem Cells Research
- RNA and protein synthesis mechanisms
- Mitochondrial Function and Pathology
- Lymphoma Diagnosis and Treatment
- Carcinogens and Genotoxicity Assessment
- Acute Myeloid Leukemia Research
- Epigenetics and DNA Methylation
- Genetics and Neurodevelopmental Disorders
- Cell Image Analysis Techniques
- Microtubule and mitosis dynamics
- Single-cell and spatial transcriptomics
- Advanced Fluorescence Microscopy Techniques
- Chronic Lymphocytic Leukemia Research
- Diabetes and associated disorders
- Advanced biosensing and bioanalysis techniques
CeMM Research Center for Molecular Medicine
2015-2024
Austrian Academy of Sciences
2015-2024
Comprehensive Cancer Center Vienna
2020-2024
Medical University of Vienna
2020-2024
AstraZeneca (United Kingdom)
2024
The Francis Crick Institute
2016
The Honourable Society of Lincoln's Inn
2009-2016
Cancer Research UK
2009-2014
Centre International de Recherche sur le Cancer
2005-2009
University of Sussex
2002-2004
Abstract Prime editing (PE) is a powerful genome engineering approach that enables the introduction of base substitutions, insertions and deletions into any given genomic locus. However, efficiency PE varies widely depends not only on region targeted, but also genetic background edited cell. Here, to determine which cellular factors affect efficiency, we carry out focused screen targeting 32 DNA repair factors, spanning all reported pathways. We show that, depending cell line type edit,...
Abstract The diversity of somatic mutations in human cancers can be decomposed into individual mutational signatures, patterns mutagenesis that arise because DNA damage and repair processes have occurred cells as they evolved towards malignancy. Correlations between signatures environmental exposures, enzymatic activities genetic defects been described, but are not ideal experimental systems—the exposures to different a patient’s lifetime uncontrolled any relationships observed only...
POLθ promotes repair of DNA double-strand breaks (DSBs) resulting from collapsed forks in homologous recombination (HR) defective tumors. Inactivation results synthetic lethality with the loss HR genes BRCA1/2, which induces under-replicated accumulation. However, it is unclear whether POLθ-dependent replication prevents HR-deficiency-associated lethality. Here, we isolated Xenopus laevis and showed that processes stalled Okazaki fragments, directly visualized by electron microscopy, thereby...
Polymerase theta (POLθ) is an error-prone DNA polymerase whose loss synthetically lethal in cancer cells bearing breast susceptibility proteins 1 and 2 (BRCA1/2) mutations. To investigate the basis of this genetic interaction, we utilized a small-molecule inhibitor targeting POLθ domain. We found that processes single-stranded (ssDNA) gaps emerge absence BRCA1, thus promoting unperturbed replication fork progression survival BRCA1 mutant cells. A genome-scale CRISPR-Cas9 knockout screen...
Tumor formation is a multistep process during which cells acquire genetic and epigenetic changes until they reach fully transformed state. We show that CDK6 contributes to tumor by regulating transcriptional responses in stage-specific manner. In early stages, the kinase induces complex program block p53 hematopoietic cells. Cells lacking function are required mutate TP53 (encoding p53) achieve immortalized binds promoters of genes including antagonists Prmt5, Ppm1d, Mdm4 The findings...
Significance Human gut microbes form a complex community with vast biosynthetic potential. Microbial products and metabolites released in the impact human health disease. However, defining causative relationships between specific bacterial disease initiation progression remains an immense challenge. This study advances understanding of functional capacity microbiota by determining presence, concentration, spatial temporal variability two enterotoxic produced gut-resident Klebsiella oxytoca ....
Abstract Immune responses need to be controlled tightly prevent autoimmune diseases, yet underlying molecular mechanisms remain partially understood. Here, we identify biallelic mutations in three patients from two unrelated families differentially expressed FDCP6 homolog (DEF6) as the cause of an inborn error immunity with systemic autoimmunity. Patient T cells exhibit impaired regulation CTLA-4 surface trafficking associated reduced functional availability, which is replicated DEF6...
While cellular metabolism impacts the DNA damage response, a systematic understanding of metabolic requirements that are crucial for repair has yet to be achieved. Here, we investigate enzymes and processes essential resolution damage. By integrating functional genomics with chromatin proteomics metabolomics, provide detailed description interplay between response. Further analysis identified Peroxiredoxin 1, PRDX1, contributes repair. During PRDX1 translocates nucleus where it reduces...
Polymerase δ is essential for eukaryotic genome duplication and synthesizes DNA at both the leading lagging strands. The polymerase complex a heterotetramer comprising catalytic subunit POLD1 accessory subunits POLD2, POLD3, POLD4. Beyond replication, has emerged as central element in maintenance. essentiality of constrained generation δ–knockout cell lines or model organisms and, therefore, understanding complexity its activity function subunits. To our knowledge, no germline biallelic...
Mismatch repair (MMR) is a crucial DNA pathway that maintains genomic integrity by correct- ing replication errors and various forms of damage. MMR deficiency (MMRd) leads to increased mutation rates, microsatellite instability, contributes tumorigenesis in multiple cancer types. Using CRISPR-Cas9-mediated knockout assay human isogenic cell lines, we characterised mutational profiles MMR-deficient cells. Our findings revealed expected increases burden the emergence known MMR-associated...
Inhibitors of the protein kinase WEE1 have emerged as promising agents for cancer therapy. In this study, we uncover synergistic interactions between small-molecule inhibitors and defects in mRNA translation, mediated by activation integrated stress response (ISR) through GCN2. Using a pooled CRISPRi screen, identify GSPT1 ALKBH8 factors whose depletion confer hypersensitivity to inhibitor, AZD1775. We demonstrate that synergy depends on ISR activation, which is induced off-target activity...
Abstract Lung cancer is the leading cause of deaths, and effective treatments are urgently needed. Loss-of-function mutations in DNA damage response kinase ATM common lung adenocarcinoma but directly targeting these with drugs remains challenging. Here we report that loss-of-function synthetic lethal inhibiting central growth factor kinases MEK1/2, including FDA-approved drug trametinib. cells resistant to MEK inhibition become highly sensitive upon loss both vitro vivo . Mechanistically,...
Recurrent gain-of-function mutations in the transcription factors STAT5A and much more STAT5B were found hematopoietic malignancies with highest proportion mature T- natural killer-cell neoplasms (peripheral T-cell lymphoma, PTCL). No targeted therapy exists for these heterogeneous often aggressive diseases. Given shortage of models PTCL, we mimicked graded or activity by expressing hyperactive Stat5a variants at low high levels system transgenic mice. Only mice developed a lethal disease...
Defects in DNA repair can cause various genetic diseases with severe pathological phenotypes. Fanconi anemia (FA) is a rare disease characterized by bone marrow failure, developmental abnormalities, and increased cancer risk that caused defective of interstrand crosslinks (ICLs). Here, we identify the deubiquitylating enzyme USP48 as synthetic viable for FA-gene deficiencies performing genome-wide loss-of-function screens across panel human haploid isogenic FA-defective cells (FANCA, FANCC,...
Ataxia telangiectasia mutated (ATM) protein kinase activation by DNA double-strand breaks (DSBs) requires the Mre11-Rad50-NBS1 (MRN) complex, whereas ATM interactor (ATMIN) is required for signaling induced changes in chromatin structure. We show here that NBS1 and ATMIN proteins compete binding this mechanism controls function. DSB-induced substrate phosphorylation was increased atmin mutant cells. Conversely, deficiency resulted ATMIN-dependent signaling. Thus, absence of one cofactor flux...