A5060457182- CRISPR and Genetic Engineering
- DNA Repair Mechanisms
- Genetics, Aging, and Longevity in Model Organisms
- Chromosomal and Genetic Variations
- DNA and Nucleic Acid Chemistry
- RNA Research and Splicing
- Mitochondrial Function and Pathology
- Genomics and Chromatin Dynamics
- Pluripotent Stem Cells Research
- Photosynthetic Processes and Mechanisms
- Plant tissue culture and regeneration
- Advanced biosensing and bioanalysis techniques
- RNA modifications and cancer
- Plant Molecular Biology Research
- Microtubule and mitosis dynamics
- PARP inhibition in cancer therapy
- Fungal and yeast genetics research
- Evolution and Genetic Dynamics
- Animal Genetics and Reproduction
- RNA and protein synthesis mechanisms
- RNA regulation and disease
- Genomics and Phylogenetic Studies
- Selenium in Biological Systems
- Insect symbiosis and bacterial influences
- Virus-based gene therapy research
Leiden University Medical Center
2015-2025
Leiden University
1997-2024
Shandong Jianzhu University
2021
The Netherlands Cancer Institute
2013
Universitair Ziekenhuis Brussel
2011
Royal Netherlands Academy of Arts and Sciences
2008-2009
Hubrecht Institute for Developmental Biology and Stem Cell Research
2002-2007
University of Cambridge
2003
Wellcome Trust
2003
Wellcome/Cancer Research UK Gurdon Institute
2003
To identify approaches to target DNA repair vulnerabilities in cancer, we discovered nanomolar potent, selective, low molecular weight (MW), allosteric inhibitors of the polymerase function Polθ, including ART558. ART558 inhibits major Polθ-mediated process, Theta-Mediated End Joining, without targeting Non-Homologous Joining. In addition, elicits damage and synthetic lethality BRCA1- or BRCA2-mutant tumour cells enhances effects a PARP inhibitor. Genetic perturbation screening revealed that...
Abstract CRISPR-Cas9 genome editing has potential to cure diseases without current treatments, but therapies must be safe. Here we show that can introduce unintended mutations in vivo, which are passed on the next generation. By fertilized zebrafish eggs using four guide RNAs selected for off-target activity vitro, followed by long-read sequencing of DNA from >1100 larvae, juvenile and adult fish across two generations, find structural variants (SVs), i.e., insertions deletions ≥50 bp,...
Recent genetical genomics studies have provided intimate views on gene regulatory networks. Gene expression variations between genetically different individuals been mapped to the causal regions, termed quantitative trait loci. Whether environment-induced plastic response of also shows heritable difference has not yet studied. Here we show that differential induced by temperatures 16 °C and 24 a strong genetic component in Caenorhabditis elegans recombinant inbred strains derived from cross...
An RNA interference (RNAi)-based genome-wide screen was performed to detect genes that contribute genome stability in somatic cells of Caenorhabditis elegans . We identified 61 such genes; these also affect spontaneous mutagenesis the germ line. Their sequence suggests a role DNA repair and/or replication, chromatin remodeling, or cell cycle control; there are many novel highly conserved from yeast human. Because known mutator causally involved hereditary and sporadic human cancers, it is...
Abstract The generation of genetic mutants in Caenorhabditis elegans has long relied on the selection mutations large-scale screens. Directed mutagenesis specific loci genome would greatly speed up analysis gene function. Here, we adapt CRISPR/Cas9 system to generate at sites C. genome.
DNA lesions that block replication fork progression are drivers of cancer-associated genome alterations, but the error-prone repair mechanisms acting on collapsed incompletely understood, and their contribution to evolution largely unexplored. Here, through whole-genome sequencing animal populations were clonally propagated for more than 50 generations, we identify a distinct class deletions spontaneously accumulate in C. elegans strains lacking translesion synthesis (TLS) polymerases....
Article5 September 2014Open Access FANCJ promotes DNA synthesis through G-quadruplex structures Pau Castillo Bosch Hubrecht Institute-KNAW, University Medical Center Utrecht & Cancer GenomiCs Netherlands, Utrecht, The Netherlands Search for more papers by this author Sandra Segura-Bayona Wouter Koole Leiden Center, Leiden, Jane T van Heteren James M Dewar Harvard School, Boston, MA, USA Marcel Tijsterman Corresponding Author Puck Knipscheer Information Bosch1, Segura-Bayona1, Koole2,...
Article27 October 2017Open Access Transparent process Mutational signatures of non-homologous and polymerase theta-mediated end-joining in embryonic stem cells Joost Schimmel orcid.org/0000-0002-2620-4349 Department Human Genetics, Leiden University Medical Center, Leiden, The Netherlands Search for more papers by this author Hanneke Kool Robin van Schendel Marcel Tijsterman Corresponding Author [email protected] orcid.org/0000-0001-8465-9002 Information Schimmel1, Kool1, Schendel1 *,1...
Abstract Faithful DNA replication is vital to prevent disease-causing mutations, chromosomal aberrations and malignant transformation. However, accuracy conflicts with pace flexibility cells rely on specialized polymerases helicases ensure effective timely of genomes that contain lesions or secondary structures. If how can tolerate a permanent barrier is, however, unknown. Here we show single unresolved G-quadruplexed structure persist through multiple mitotic divisions without changing...
Off-target or random integration of exogenous DNA hampers precise genomic engineering and presents a safety risk in clinical gene therapy strategies. Genetic definition has been lacking for decades. Here, we show that the A-family polymerase θ (Pol θ) promotes integration, while canonical non-homologous end joining plays secondary role; cells double deficient are devoid any events, demonstrating these two mechanisms define integration. In contrast, homologous recombination is not reduced...
Abstract Cells are protected from toxic DNA double-stranded breaks (DSBs) by a number of repair mechanisms, including some that intrinsically error prone, thus resulting in mutations. To what extent these mechanisms contribute to evolutionary diversification remains unknown. Here, we demonstrate the A-family polymerase theta (POLQ) is major driver inheritable genomic alterations Caenorhabditis elegans . Unlike somatic cells, which use non-homologous end joining (NHEJ) transposon-induced...
Gene editing through repair of CRISPR-Cas9-induced chromosomal breaks offers a means to correct wide range genetic defects. Directing produce desirable outcomes by modulating DNA pathways holds considerable promise increase the efficiency genome engineering. Here, we show that inhibition non-homologous end joining (NHEJ) or polymerase theta-mediated (TMEJ) can be exploited alter mutational CRISPR-Cas9. We robust TMEJ activity at double-strand (DSBs) using ART558, potent theta (Polϴ)...
Posttranscriptional gene silencing in Caenorhabditis elegans results from exposure to double-stranded RNA (dsRNA), a phenomenon designated as interference (RNAi), or co-suppression, which transgenic DNA leads of both the transgene and endogenous gene. Here we show that single-stranded oligomers antisense polarity can also be potent inducers silencing. As is case for RNAs act independently RNAi genes rde-1 rde-4 but require mutator/RNAi mut-7 putative DEAD box helicase, mut-14. Our data favor...