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Articles by Daniel Schramek
Aneuploidy selects for the acquisition of driver genes in breast cancer
Abstract Chromosome instability is highly prevalent in cancer and drives large-scale chromosomal imbalances, known as aneuploidies1,2,3,4. How aneuploidy contributes to tumorigenesis remains difficult to study due to the vast numbers of genes affected. Here we established a CRISPR knockout- and activation-linked assay (CRISPR-KOALA), enabling high-throughput bidirectional genetic screens in immunocompetent mouse models of cancer.
Systematic discovery of pathogen effector functions across human pathogens and pathways
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We next performed four additional screens representing pathways that are broadly relevant: p53 signaling, STING signaling, apoptosis, and major histocompatibility complex class I (MHC-I) antigen presentation. The p53 tumor suppressor regulates cell cycle progression, apoptosis, and the DNA damage response and is a frequent target of viral oncogenes.66 The cGAS-STING pathway acts as the major innate immune sensor for cytoplasmic double-stranded DNA (dsDNA).
By Tomas Pachano, He Leng, Guillaume Dugied, Travis Tribble, Vincent LOUBIERE, Yeojin Lee, Felix Rauh, Victor A Manon, Kevin Yuan, Jocelyn Nurtanto, Alexander Schleiffer, Veronika Young, Benjamin Weller Verified, Eleanor Lyons, Matthew R. Hass, Leah C. Kottyan, Matthew T Weirauch, Juan Bass, Hayley J. Newton, Alexander W Ensminger, Pascal Falter-Braun, Jue Chen, Daniel Schramek, Mikko Taipale, Alexander Stark
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Cell Press
Verified
Topoisomerase IIb binding delineates localized mutational processes and driver mutations in cancer genomes - Nature Communications
Abstract Type-II topoisomerases resolve topological stress in DNA through double-strand breaks. While topoisomerases are chemotherapy targets linked to therapy-related genotoxicity, TOP2B is uniquely positioned to influence mutagenesis through its activity in non-dividing cells and sensitivity to topoisomerase poisons.
Cell cycle duration determines oncogenic transformation capacity - Nature
Abstract Oncogenic mutations are widespread in normal human tissues1. Similarly, in murine chimeras, cells carrying an oncogenic lesion contribute normal cells to adult tissues without causing cancer2,3,4. How lineages that escape cancer via normal development differ from the minority that succumb is unclear. Tumours exhibit characteristic cancer hallmarks; we therefore searched for hallmarks that differentiate cancer-prone lineages from resistant lineages.
TRIM28-dependent developmental heterogeneity determines cancer susceptibility through distinct epigenetic states - Nature Cancer
Abstract Mutations in cancer risk genes increase susceptibility, but not all carriers develop cancer. Indeed, while DNA mutations are necessary drivers of cancer, only a small subset of mutated cells go on to cause the disease. To date, the mechanisms underlying individual cancer susceptibility remain unclear.
CRISPR-StAR enables high-resolution genetic screening in complex in vivo models - Nature Biotechnology
Abstract Pooled genetic screening with CRISPR–Cas9 has enabled genome-wide, high-resolution mapping of genes to phenotypes, but assessing the effect of a given genetic perturbation requires evaluation of each single guide RNA (sgRNA) in hundreds of cells to counter stochastic genetic drift and obtain robust results.
In vivo CRISPR screens identify a dual function of MEN1 in regulating tumor–microenvironment interactions - Nature Genetics
Abstract Functional genomic screens in two-dimensional cell culture models are limited in identifying therapeutic targets that influence the tumor microenvironment. By comparing targeted CRISPR–Cas9 screens in a two-dimensional culture with xenografts derived from the same cell line, we identified MEN1 as the top hit that confers differential dropout effects in vitro and in vivo.
Proteome-scale discovery of protein degradation and stabilization effectors - Nature
Abstract Targeted protein degradation and stabilization are promising therapeutic modalities because of their potency, versatility and their potential to expand the druggable target space1,2. However, only a few of the hundreds of E3 ligases and deubiquitinases in the human proteome have been harnessed for this purpose, which substantially limits the potential of the approach.
A designer peptide against the EAG2–Kvβ2 potassium channel targets the interaction of cancer cells and neurons to treat glioblastoma - Nature Cancer
Abstract Glioblastoma (GBM) is an incurable brain cancer that lacks effective therapies. Here we show that EAG2 and Kvβ2, which are predominantly expressed by GBM cells at the tumor–brain interface, physically interact to form a potassium channel complex due to a GBM-enriched Kvβ2 isoform. In GBM cells, EAG2 localizes at neuron-contacting regions in a Kvβ2-dependent manner.
Recognition of Semaphorin Proteins by P. sordellii Lethal Toxin Reveals Principles of Receptor Specificity in Clostridial Toxins
Highlights • CRISPR screen identifies SEMA6A and SEMA6B as receptors for P. sordellii lethal toxin TcsL • Soluble SEMA6A ectodomain protects mouse lungs from TcsL-induced edema • 3.3 Å cryo-EM structure of TcsL bound to SEMA6A reveals atomic details of the interaction • 15 mutations in the TcsL receptor-binding interface rewire receptor specificity Summary Pathogenic clostridial species secrete potent toxins that induce severe host tissue damage.
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