A5058207730- DNA Repair Mechanisms
- CRISPR and Genetic Engineering
- Genomics and Chromatin Dynamics
- Microtubule and mitosis dynamics
- Epigenetics and DNA Methylation
- Genomic variations and chromosomal abnormalities
- Glioma Diagnosis and Treatment
- Genomics and Phylogenetic Studies
- Genetics and Neurodevelopmental Disorders
- RNA and protein synthesis mechanisms
- Fungal and yeast genetics research
- Telomeres, Telomerase, and Senescence
- Cancer therapeutics and mechanisms
- Plant Genetic and Mutation Studies
- Photosynthetic Processes and Mechanisms
- Renal and related cancers
- Chromatin Remodeling and Cancer
- Chromosomal and Genetic Variations
University of Oxford
2018-2023
CRUK/MRC Oxford Institute for Radiation Oncology
2018-2023
University of Sussex
2019
Cardiff University
2012-2013
The INO80 chromatin remodeling complex functions in transcriptional regulation, DNA repair, and replication. Here we uncover a novel role for regulating chromosome segregation. First, show that the conserved Ies6 subunit is critical function vivo. Strikingly, found loss of either or Ino80 catalytic results rapid increase ploidy. One route to polyploidy through missegregation due aberrant centromere structure, leads defective Importantly, structure flanking centromeres altered cells lacking...
The RSC chromatin remodeling complex has been implicated in contributing to DNA double-strand break (DSB) repair a number of studies. Both survival and levels H2A phosphorylation response damage are reduced the absence RSC. Importantly, there is evidence for two isoforms this complex, defined by presence either Rsc1 or Rsc2. Here, we investigated whether provide distinct contributions responses. First, established that differ Rsc2 but otherwise have same subunit composition. We found both...
Replication stress is a common feature of cancer cells, and thus potentially important therapeutic target. Here, we show that cyclin-dependent kinase (CDK)-induced replication stress, resulting from Wee1 inactivation, synthetic lethal with mutations disrupting dNTP homeostasis in fission yeast. inactivation leads to increased demand through CDK-induced firing dormant origins. Subsequent depletion inefficient DNA replication, damage genome instability. Cells respond this by increasing supply...
Abstract Preclinical models of cancer have demonstrated enhanced efficacy cell-cycle checkpoint kinase inhibitors when used in combination with genotoxic agents. This therapy is predicted to be exquisitely toxic cells a deficient G1–S or genetic predisposition leading intrinsic DNA replication stress, as these become fully dependent on the intra-S and G2–M checkpoints for repair cellular survival. Therefore, abolishing remaining after damage leads increased cell death tumor cell–specific...
The healing of broken chromosomes by de novo telomere addition, while a normal developmental process in some organisms, has the potential to cause extensive loss heterozygosity, genetic disease, or cell death. However, it is unclear how addition (dnTA) regulated at DNA double-strand breaks (DSBs). Here, using non-essential minichromosome fission yeast, we identify roles for HR factors Rqh1 helicase, concert with Rad55, suppressing dnTA near DSB. We find frequency rqh1Δ rad55Δ cells reduced...
Abstract Chromosomal instability (CIN) drives cell-to-cell heterogeneity, and the development of genetic diseases, including cancer. Impaired homologous recombination (HR) has been implicated as a major driver CIN, however, underlying mechanism remains unclear. Using fission yeast model system, we establish common role for HR genes in suppressing DNA double-strand break (DSB)-induced CIN. Further, show that an unrepaired single-ended DSB arising from failed repair or telomere loss is potent...
Abstract Replication stress is a common feature of cancer cells, and thus potentially important therapeutic target. Here we show that CDK-induced replication synthetic lethal with mutations disrupting dNTP homeostasis in fission yeast. Wee1 inactivation leads to increased demand through firing dormant origins. Subsequent depletion inefficient DNA replication, Mus81-dependent damage, genome instability. Cells respond this by increasing supply Set2-dependent MBF-induced expression Cdc22, the...
Abstract WEE1 inhibitors have now advanced into clinical studies as monotherapy or in combination with chemoradiotherapy TP53, RAS, BRAF , and SETD2 mutation carriers across several tumour types, yet mechanisms of resistance are still poorly understood. Here, we further elucidate the by which AZD1775, most potent inhibitor, kills cells reveal additional genetic interactions that can result resistance, but could be used to optimise its utility. We identified RNA Polymerase II-associated...
Abstract Persistent DNA damage arising from unrepaired broken chromosomes or telomere loss can promote checkpoint adaptation, and cell cycle progression, thereby increasing survival but also genome instability. However, the nature extent of such instability is unclear. We show, using Schizosaccharomyces pombe , that inherited chromosomes, failed homologous recombination repair, are subject to cycles se gregation, r eplication extensive end- p rocessing, termed here SERPent cycles, by...