A5011950947- DNA Repair Mechanisms
- Genomics and Chromatin Dynamics
- CRISPR and Genetic Engineering
- Cytomegalovirus and herpesvirus research
- Cancer Genomics and Diagnostics
- Advanced biosensing and bioanalysis techniques
- Ubiquitin and proteasome pathways
- Epigenetics and DNA Methylation
- RNA Interference and Gene Delivery
- RNA Research and Splicing
- Genetics, Aging, and Longevity in Model Organisms
- Mitochondrial Function and Pathology
- Smart Grid and Power Systems
- DNA and Nucleic Acid Chemistry
- Smart Grid Security and Resilience
- Power System Reliability and Maintenance
Cardiff University
2015-2025
Cancer Genetics (United States)
2024
Constellation Pharmaceuticals (United States)
2018
Leiden University
2008
CRISPR-Cas9 is a powerful gene-editing technology; however, off-target activity remains an important consideration for therapeutic applications. We have previously shown that force-stretching DNA induces and hypothesized distortions of the topology in vivo, such as negative supercoiling, could reduce Cas9 specificity. Using single-molecule optical-tweezers, we demonstrate supercoiling λ-DNA sequence-specific binding at multiple sites, even low forces. adapted CIRCLE-seq approach, detect over...
Abstract Understanding how breaks form and are repaired in the genome depends on accurate measurement of frequency position DNA double strand (DSBs). This is crucial for identification a chemical’s damage potential safe development therapies, including editing technologies. Current DSB sequencing methods suffer from high background levels, inability to accurately measure low endogenous costs. Here we describe INDUCE-seq, which overcomes these problems, detecting simultaneously presence...
Background : Signaling by estrogen-receptor alpha (ERα) plays a major role in breast cancer initiation and ERα-mediated DNA damage has been implicated development of resistance to endocrine therapies. Investigations the mechanism mediated ERα signaling are carried out cell lines due lack ERα+ normal human epithelial cells (HBEC). Defining mechanisms which induces initiates tumorigenesis requires HBECs that express ERα, demonstrate estrogenic responses, amenable long term propagation culture....
The rates at which lesions are removed by DNA repair can vary widely throughout the genome, with important implications for genomic stability. To study this, we measured distribution of nucleotide excision (NER) UV-induced budding yeast genome. By plotting these in relation to genes and their associated flanking sequences, reveal that, normal cells, display a distinctive pattern, suggesting that is highly organized within Furthermore, comparing genome-wide wild-type cells defective global...
The interplay between active biological processes and DNA repair is central to mutagenesis. Here, we show that the ubiquitous process of replication initiation mutagenic, leaving a specific mutational footprint at thousands early efficient origins. observed pattern consistent with two distinct mechanisms, reflecting two-step origin activation, triggering formation breaks center origins local error-prone synthesis in their immediate vicinity. We demonstrate these initiation-dependent exert an...
Regulating gene expression programmes is a central facet of the DNA damage response. The Dun1 kinase protein controls many induced genes, including ribonucleotide reductase which regulate cellular dNTP pools. Using combination profiling and chromatin immunoprecipitation, we demonstrate that in absence yeast Rad4–Rad23 nucleotide excision repair complex binds to promoters certain response genes DUN1, inhibiting their expression. UV radiation promotes loss occupancy from regulatory regions...
Repair of UV-induced DNA damage requires chromatin remodeling. How repair is initiated in remains largely unknown. We recently demonstrated that global genome–nucleotide excision (GG-NER) organized into domains relation to open reading frames. Here, we define these domains, identifying the genomic locations from which initiated. By examining damage–induced changes linear structure nucleosomes at sites, demonstrate how remodeling during GG-NER. In undamaged cells, show GG-NER complex occupies...
Mammalian DNA replication employs several RecQ helicases to orchestrate the faithful duplication of genetic information. Helicase function is often coupled activity specific nucleases, but how helicase and nuclease activities are co-directed unclear. Here we identify inactive ubiquitin-specific protease, USP50, as a ubiquitin-binding chromatin-associated protein required for ongoing replication, fork restart, telomere maintenance cellular survival during replicative stress. USP50 supports...
Abstract Mammalian DNA replication relies on various helicase and nuclease activities to ensure accurate genetic duplication, but how different are properly directed remains unclear. Here, we identify the ubiquitin-specific protease, USP50, as a chromatin-associated protein required promote ongoing replication, fork restart, telomere maintenance, cellular survival following hydroxyurea or pyridostatin treatment, suppression of breaks near GC-rich sequences. We find that USP50 supports proper...
Abstract DNA G-quadruplexes (G4s) are secondary structures with significant roles in regulating genome function and stability. Dysregulation of the dynamic formation G4s is linked to genomic instability disease, but underlying mechanisms not fully understood. In this study, we conducted a screen chromatin-modifying enzymes identified nine potential inhibitors G4 formation, including seven that were previously characterized. Among these, highlight role BAZ2 chromatin remodelers as key...
Abstract Understanding how breaks form and are repaired in the genome depends on accurate measurement of frequency position DNA double strand (DSBs). This is crucial for identification a chemical’s damage potential safe development therapies, including editing technologies. Current DSB sequencing methods suffer from high background levels, inability to accurately measure low endogenous costs. Here we describe INDUCE-seq, which overcomes these problems, detecting simultaneously presence...
Abstract The rates at which lesions are removed by DNA repair can vary widely throughout the genome with important implications for genomic stability. To study this, we measured distribution of nucleotide excision (NER) UV-induced budding yeast genome. By plotting these in relation to genes and their associated flanking sequences, reveal that normal cells, display a distinctive pattern, suggesting is highly organised within Furthermore, comparing genome-wide wild-type cells defective global...
Abstract Repair of UV-induced DNA damage requires chromatin remodeling. How repair is initiated in remains largely unknown. We recently demonstrated that Global Genome Nucleotide Excision (GG-NER) organized into domains around open reading frames. Here, we identify these domains, and by examining damage-induced changes the linear structure nucleosomes, demonstrate how remodeling during repair. In undamaged cells, show GG-NER complex occupies at nucleosome free regions specific gene...
The increasingly more dynamic behaviour of the grid, for example due to proliferation Distributed Energy Resources (DER) and Electric Vehicles (EV), necessitates need monitor distribution part grid (near) realtime. Therefore, progressively sensors can be found in that grid. Consequently, much data, hence alarm messages will sent DNO/DSO's control centres. Detection critical events from a vast stream massages is time-consuming task when done manually. This may increase CAIDI metric...