A5011587437- DNA Repair Mechanisms
- CRISPR and Genetic Engineering
- Genetics, Aging, and Longevity in Model Organisms
- PARP inhibition in cancer therapy
- Telomeres, Telomerase, and Senescence
- Cancer therapeutics and mechanisms
- Fungal and yeast genetics research
- Bacterial Genetics and Biotechnology
- Cell death mechanisms and regulation
- Genomics and Phylogenetic Studies
- Genomics and Chromatin Dynamics
- Cancer-related Molecular Pathways
- Biochemical and Molecular Research
- Enzyme Structure and Function
- Plant Genetic and Mutation Studies
- Carcinogens and Genotoxicity Assessment
- Cancer Immunotherapy and Biomarkers
- RNA and protein synthesis mechanisms
- Microtubule and mitosis dynamics
Cardiff University
2017-2024
Newcastle University
2008-2017
Queen's Medical Centre
2003-2017
University of Nottingham
2003-2017
John Radcliffe Hospital
2007-2009
University of Oxford
2007-2009
Newcastle Hospitals - Campus for Ageing and Vitality
2008
Cancer Research UK
2007
ABSTRACT Since most archaea are extremophilic and difficult to cultivate, our current knowledge of their biology is confined largely comparative genomics biochemistry. Haloferax volcanii offers great promise as a model organism for archaeal genetics, but until now there has been lack wide variety selectable markers this organism. We describe here isolation H. leuB trpA genes encoding 3-isopropylmalate dehydrogenase tryptophan synthase, respectively, development these positive selection...
Abstract DNA-RNA hybrid structures have been detected at the vicinity of DNA double-strand breaks (DSBs) occurring within transcriptional active regions genome. The induction hybrids strongly affects repair these DSBs, but nature and how they are formed remain poorly understood. Here we provide evidence that R loops, three-stranded containing displaced single-stranded (ssDNA) can form sub-telomeric DSBs. These loops generated independently resection induced alongside two-stranded on ssDNA by...
CSM2, PSY3, SHU1, and SHU2 (collectively referred to as the SHU genes) were identified in Saccharomyces cerevisiae four genes same epistasis group that suppress various sgs1 top3 mutant phenotypes when mutated. Although have been implicated homologous recombination repair (HRR), their precise role(s) within this pathway remains poorly understood. Here, we a specific role for Shu proteins Rad51/Rad54-dependent HRR pathway(s) MMS-induced lesions during S-phase. We show that, although mutation...
Polyploidy is frequent in nature and a hallmark of cancer cells, but little known about the strategy DNA repair polyploid organisms. We have studied archaeon Haloferax volcanii, which contains up to 20 genome copies. focused on role Mre11 Rad50 proteins, are found all domains life form complex that binds coordinates double-strand breaks (DSBs). Surprisingly, mre11 rad50 mutants more resistant damage than wild-type. However, wild-type cells recover faster from damage, pulsed-field gel...
To better understand telomere biology in budding yeast, we have performed systematic suppressor/enhancer analyses on yeast strains containing a point mutation the essential capping gene CDC13 (cdc13-1) or null DNA damage response and YKU70 (yku70Δ). We Quantitative Fitness Analysis (QFA) thousands of mutations affecting telomere-capping proteins combination with library deletion mutations. perform QFA, typically inoculate 384 separate cultures onto solid agar plates monitor growth each...
DNA-end resection, the generation of single-stranded DNA at double strand break (DSB) ends, is critical for controlling many cellular responses to breaks. Here we show that conserved damage checkpoint sliding clamp (the 9-1-1 complex) plays two opposing roles coordinating DSB resection in budding yeast. We major effect inhibit by promoting recruitment Rad953BP1 near DSBs. However, also stimulates Exo1- and Dna2-Sgs1-dependent nuclease/helicase activities, this can be observed absence...
Esc2 is a member of the RENi family SUMO-like domain proteins and implicated in gene silencing Saccharomyces cerevisiae. Here, we identify dual role for during S-phase mediating both intra-S-phase DNA damage checkpoint signaling preventing accumulation Rad51-dependent homologous recombination repair (HRR) intermediates. These roles are qualitatively similar to those Sgs1, yeast ortholog human Bloom's syndrome protein, BLM. However, whereas mutation either ESC2 or SGS1 leads unprocessed HRR...
Single-stranded DNA (ssDNA) at ends is an important regulator of the damage response. Resection, generation ssDNA, affects checkpoint activation, repair pathway choice, ssDNA-associated mutation and replication fork stability. In eukaryotes, extensive resection requires nuclease Exo1 nuclease/helicase pair: Dna2 Sgs1BLM. How Dna2-Sgs1BLM coordinate during remains poorly understood. The clamp (the 9-1-1 complex) has been reported to play role in stimulating but exact mechanism unclear. Here...
Maintenance of telomere capping is absolutely essential to the survival eukaryotic cells. Telomere proteins, such as Cdc13 and POT1, are for viability budding yeast mammalian cells, respectively. Here we identify, first time, three genetic modifications that allow cells survive without by Cdc13. We found simultaneous inactivation Sgs1, Exo1, Rad9, DNA damage response (DDR) sufficient cell division in absence Quantitative amplification ssDNA (QAOS) was used show RecQ helicase Sgs1 plays an...
Homologous recombination is a fundamental cellular process that rearranges genes both within and between chromosomes, promotes repair of damaged DNA underpins replication. Much our understanding stems from pioneering studies bacterial eukaryotic systems such as Escherichia coli Saccharomyces cerevisiae. Since most archaeal species are extremophilic difficult to cultivate, current knowledge in the Archaea confined largely comparative genomics biochemistry. A clear view what we can learn will...
Homologous recombination plays a central role in the repair of double-strand DNA breaks, restart stalled replication forks and generation genetic diversity. Regulation is essential since defects can lead to genome instability chromosomal rearrangements. Strand exchange key step - it catalysed by RecA bacteria, Rad51/Dmc1 eukaryotes RadA archaea. RadB, paralogue RadA, present many archaeal species. RadB has previously been proposed function as mediator, assisting RadA-mediated strand...
// Greg Ngo 1 , Sam Hyatt Julia Grimstead Rhiannon Jones Eric Hendrickson 2 Chris Pepper 3 and Duncan Baird Division of Cancer Genetics, School Medicine, Cardiff University, Heath Park, Cardiff, UK Department Biochemistry, Molecular Biology, Biophysics, University Minnesota, Minneapolis, MN, USA Sussex, Brighton Sussex Medical School, Brighton, Correspondence to: Baird, email: bairddm@cardiff.ac.uk Keywords: telomere; genome instability; PARP1; crisis; cancer Received: August 19,...
Functional telomeres are critically important to eukaryotic genetic stability. Scores of proteins and pathways known affect telomere function. Here, we report a series related genome-wide interaction screens performed on budding yeast cells with acute or chronic defects. Genetic interactions were examined in defective Cdc13 Stn1, affecting two components CST, single stranded DNA (ssDNA) binding complex that binds telomeric DNA. For comparison, also defects Rfa3, the major ssDNA protein, RPA,...
Abstract Functional telomeres are critically important to eukaryotic genetic stability. Budding yeast is a powerful model organism for analysis and maintained by very similar mechanisms human telomeres. Scores of proteins pathways known affect telomere function. Here, we report series related genome-wide interaction screens performed on budding cells with acute or chronic defects. We examined interactions in defective Cdc13 Stn1, affecting two components CST, single stranded DNA (ssDNA)...
Abstract Objective The proto-oncogene BCL-3 is upregulated in a subset of colorectal cancers (CRC) and increased expression the gene correlates with poor patient prognosis. aim to investigate whether inhibiting can increase response DNA damage CRC. Design function was studied vitro using siRNA CRISPR-Cas9 genome editing vivo Bcl3 -/- mice. induced by γ-irradiation and/or cisplatin quantified H2AX RAD51 foci, repair pathways investigated HR/NHEJ assays treatment PARP inhibitor olaparib....