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  • 1
    Language: English
    In: Cell reports (Cambridge), 2014-04-10, Vol.7 (1), p.53-61
    Description: The firing of eukaryotic origins of DNA replication requires CDK and DDK kinase activities. DDK, in particular, is involved in setting the temporal program of origin activation, a conserved feature of eukaryotes. Rif1, originally identified as a telomeric protein, was recently implicated in specifying replication timing in yeast and mammals. We show that this function of Rif1 depends on its interaction with PP1 phosphatases. Mutations of two PP1 docking motifs in Rif1 lead to early replication of telomeres in budding yeast and misregulation of origin firing in fission yeast. Several lines of evidence indicate that Rif1/PP1 counteract DDK activity on the replicative MCM helicase. Our data suggest that the PP1/Rif1 interaction is downregulated by the phosphorylation of Rif1, most likely by CDK/DDK. These findings elucidate the mechanism of action of Rif1 in the control of DNA replication and demonstrate a role of PP1 phosphatases in the regulation of origin firing.
    Subject(s): Animals ; Cell Cycle Proteins - metabolism ; DNA Replication - physiology ; Phosphorylation ; Protein Phosphatase 1 - metabolism ; Protein-Serine-Threonine Kinases - metabolism ; Replication Origin - physiology ; Report ; Repressor Proteins - genetics ; Repressor Proteins - metabolism ; Saccharomyces cerevisiae ; Saccharomyces cerevisiae - metabolism ; Saccharomyces cerevisiae Proteins - genetics ; Saccharomyces cerevisiae Proteins - metabolism ; Schizosaccharomyces - metabolism ; Schizosaccharomyces pombe ; Telomere - metabolism ; Telomere-Binding Proteins - genetics ; Telomere-Binding Proteins - metabolism
    ISSN: 2211-1247
    E-ISSN: 2211-1247
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
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  • 2
    Language: English
    In: Nucleic acids research, 2020-02-20, Vol.48 (3), p.1271-1284
    Description: Abstract 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 of heterozygosity, genetic disease, or cell death. However, it is unclear how de novo telomere addition (dnTA) is regulated at DNA double-strand breaks (DSBs). Here, using a non-essential minichromosome in fission yeast, we identify roles for the HR factors Rqh1 helicase, in concert with Rad55, in suppressing dnTA at or near a DSB. We find the frequency of dnTA in rqh1Δ rad55Δ cells is reduced following loss of Exo1, Swi5 or Rad51. Strikingly, in the absence of the distal homologous chromosome arm dnTA is further increased, with nearly half of the breaks being healed in rqh1Δ rad55Δ or rqh1Δ exo1Δ cells. These findings provide new insights into the genetic context of highly efficient dnTA within HR intermediates, and how such events are normally suppressed to maintain genome stability.
    Subject(s): Chromosomes, Fungal - genetics ; DNA Breaks, Double-Stranded ; DNA Helicases - genetics ; DNA-Binding Proteins - genetics ; Exodeoxyribonucleases - genetics ; Gene Expression Regulation, Fungal - genetics ; Genome Integrity, Repair and ; Genome, Fungal - genetics ; Genomic Instability - genetics ; Loss of Heterozygosity - genetics ; Rad51 Recombinase - genetics ; Recombinational DNA Repair - genetics ; Schizosaccharomyces - genetics ; Schizosaccharomyces pombe Proteins - genetics ; Telomere - genetics
    ISSN: 0305-1048
    E-ISSN: 1362-4962
    Source: PubMed Central
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
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  • 3
    Language: English
    In: Clinical pharmacology and therapeutics, 2021-11, Vol.110 (5), p.1180-1189
    Description: The rapid evolution of science and technology allows innovative approaches to generate new types of evidence about the effectiveness of medical product development so as to speed up patients’ access to better diagnostics and treatment. Our study explored how two emerging approaches, the use of real‐world evidence (RWE) and complex clinical trial (CCT) design, are currently being used by the pharmaceutical industry to support premarketing authorization of medical product development and reviewed the international landscape for regulatory acceptance of such novel approaches. Combining evidence from a literature review, company survey, and interviews with international regulators and experts, we found that 80% of Europe‐based pharmaceutical companies have used RWE and 50% have used CCTs, in some capacity. Further, we present case examples of how companies are using these approaches and how international regulators are preparing for such developments. To conclude, we provide a set of recommendations for European industry and regulators to consider so that these novel approaches achieve their full potential within the EU regulatory system.
    Subject(s): Abridged Index Medicus
    ISSN: 0009-9236
    E-ISSN: 1532-6535
    Source: Get It Now
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  • 4
    Language: English
    In: EMBO reports, 2014-08, Vol.15 (8), p.871-877
    Description: Elongation of the telomeric overhang by telomerase is counteracted by synthesis of the complementary strand by the CST complex, CTC1(Cdc13)/Stn1/Ten1. Interaction of budding yeast Stn1 with overhang‐binding Cdc13 is increased by Cdc13 SUMOylation. Human and fission yeast CST instead interact with overhang‐binding TPP1/POT1. We show that the fission yeast TPP1 ortholog, Tpz1, is SUMOylated. Tpz1 SUMOylation restricts telomere elongation and promotes Stn1/Ten1 telomere association, and a SUMO‐Tpz1 fusion protein has increased affinity for Stn1. Our data suggest that SUMO inhibits telomerase through stimulation of Stn1/Ten1 action by Tpz1, highlighting the evolutionary conservation of the regulation of CST function by SUMOylation. Synopsis This study shows that Tpz1 SUMOylation in fission yeast is required for Stn1/Ten1 recruitment to telomeres and, thus, prevention of telomere elongation. Tpz1 SUMOylation increases its affinity for Stn1. Fission yeast telomere protein Tpz1, the TPP1 ortholog, is SUMOylated at lysine 242. Tpz1 SUMOylation limits telomere elongation and the association of telomerase with telomeres. As SUMOylation of budding yeast Cdc13, Tpz1 SUMOylation is required for efficient recruitment of Stn1/Ten1 to telomeres. SUMO‐mediated recruitment of Stn1 is proposed to be a conserved feature within the CST complex. This study shows that Tpz1 SUMOylation in fission yeast is required for Stn1/Ten1 recruitment to telomeres and, thus, prevention of telomere elongation. Tpz1 SUMOylation increases its affinity for Stn1.
    Subject(s): Amino Acid Sequence ; Carrier Proteins - chemistry ; Carrier Proteins - metabolism ; CST ; DNA-Binding Proteins ; Evolution, Molecular ; Genes ; Molecular Sequence Data ; Mutation ; Protein Binding ; Schizosaccharomyces - cytology ; Schizosaccharomyces - metabolism ; Schizosaccharomyces pombe Proteins - chemistry ; Schizosaccharomyces pombe Proteins - metabolism ; Scientific Reports ; Stn1 ; SUMO ; SUMO-1 Protein - metabolism ; Sumoylation ; Telomerase ; Telomerase - metabolism ; Telomere - metabolism ; Telomere Homeostasis ; Telomere-Binding Proteins - metabolism ; telomeres ; Tpz1 ; Tripeptidyl-Peptidase 1 ; Yeast
    ISSN: 1469-221X
    E-ISSN: 1469-3178
    Source: HighWire Press (Free Journals)
    Source: Wiley Online Library All Journals
    Source: PubMed Central
    Source: Get It Now
    Source: Wiley-Blackwell Full Collection 2014
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  • 5
    Language: English
    In: EMBO reports, 2014-10, Vol.15 (10), p.1093-1101
    Description: Telomerase action is temporally linked to DNA replication. Although yeast telomeres are normally late replicating, telomere shortening leads to early firing of subtelomeric DNA replication origins. We show that double‐strand breaks flanked by short telomeric arrays cause origin firing early in S phase at late‐replicating loci and that this effect on origin firing time is dependent on the Tel1ATM checkpoint kinase. The effect of Tel1ATM on telomere replication timing extends to endogenous telomeres and is stronger than that elicited by Rif1 loss. These results establish that Tel1ATM specifies not only the extent but also the timing of telomerase recruitment. Synopsis This study shows that the Tel1ATM checkpoint kinase is required in S phase for the early firing of origins of DNA replication located near short telomeres. The data indicate that Tel1ATM controls the timing of telomerase recruitment to short telomeres. Short arrays of telomeric repeats at double‐strand breaks and short telomeres in late‐replicating regions are replicated early in S phase The activity of the Tel1ATM checkpoint kinase is required for the shift to early origin firing near short telomeric arrays. Double‐strand breaks devoid of telomeric repeats do not undergo a shift in replication timing. This study shows that the Tel1ATM checkpoint kinase is required in S phase for the early firing of origins of DNA replication located near short telomeres. The data indicate that Tel1ATM controls the timing of telomerase recruitment to short telomeres.
    Subject(s): Chromatin ; Chromosomes ; Deoxyribonucleic acid ; DNA ; DNA Breaks, Double-Stranded ; DNA replication ; DNA Replication - genetics ; Intracellular Signaling Peptides and Proteins - genetics ; Intracellular Signaling Peptides and Proteins - metabolism ; Molecular biology ; origin firing ; Protein Serine-Threonine Kinases - genetics ; Protein Serine-Threonine Kinases - metabolism ; Replication Origin - genetics ; replication timing ; Repressor Proteins - genetics ; S Phase - genetics ; Saccharomyces cerevisiae ; Saccharomyces cerevisiae Proteins - genetics ; Saccharomyces cerevisiae Proteins - metabolism ; Scientific Reports ; Tel1 ; Telomerase ; Telomerase - genetics ; Telomere - genetics ; Telomere Shortening - genetics ; Telomere-Binding Proteins - genetics ; telomeres ; Yeast
    ISSN: 1469-221X
    E-ISSN: 1469-3178
    Source: HighWire Press (Free Journals)
    Source: Wiley Online Library All Journals
    Source: PubMed Central
    Source: Get It Now
    Source: Wiley-Blackwell Full Collection 2014
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  • 6
    Language: English
    Subject(s): Medical policy
    ISBN: 9789289052757
    ISBN: 9289052759
    Source: Ebook Central - Academic Complete
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  • 7
    Language: English
    In: The EMBO journal, 2009-11-04, Vol.28 (21), p.3400-3412
    Description: Loss of heterozygosity (LOH), a causal event in cancer and human genetic diseases, frequently encompasses multiple genetic loci and whole chromosome arms. However, the mechanisms by which such extensive LOH arises, and how it is suppressed in normal cells is poorly understood. We have developed a genetic system to investigate the mechanisms of DNA double‐strand break (DSB)‐induced extensive LOH, and its suppression, using a non‐essential minichromosome, Ch16, in fission yeast. We find extensive LOH to arise from a new break‐induced mechanism of isochromosome formation. Our data support a model in which Rqh1 and Exo1‐dependent end processing from an unrepaired DSB leads to removal of the broken chromosome arm and to break‐induced replication of the intact arm from the centromere, a considerable distance from the initial lesion. This process also promotes genome‐wide copy number variation. A genetic screen revealed Rhp51, Rhp55, Rhp57 and the MRN complex to suppress both isochromosome formation and chromosome loss, in accordance with these events resulting from extensive end processing associated with failed homologous recombination repair.
    Subject(s): Adenosine Triphosphatases - metabolism ; break-induced replication ; Centromere - genetics ; Chromosomes ; Chromosomes, Fungal - genetics ; Chromosomes, Fungal - metabolism ; copy number variation ; DNA Breaks, Double-Stranded ; DNA damage ; DNA-Binding Proteins - metabolism ; DSB ; Gene Conversion ; Genetic disorders ; homologous recombination ; isochromosome ; Loss of Heterozygosity ; Molecular biology ; Rad51 Recombinase - metabolism ; Schizosaccharomyces - genetics ; Schizosaccharomyces - metabolism ; Schizosaccharomyces pombe Proteins - metabolism ; Yeast
    ISSN: 0261-4189
    E-ISSN: 1460-2075
    Source: HighWire Press (Free Journals)
    Source: PubMed Central
    Source: Get It Now
    Source: Wiley-Blackwell Full Collection 2014
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  • 8
    Language: English
    In: Molecular and Cellular Biology, 2007-11-01, Vol.27 (21), p.7745-7757
    Description: Article Usage Stats Services MCB Citing Articles Google Scholar PubMed Related Content Social Bookmarking CiteULike Delicious Digg Facebook Google+ Mendeley Reddit StumbleUpon Twitter current issue Spotlights in the Current Issue MCB About MCB Subscribers Authors Reviewers Advertisers Inquiries from the Press Permissions & Commercial Reprints ASM Journals Public Access Policy MCB RSS Feeds 1752 N Street N.W. • Washington DC 20036 202.737.3600 • 202.942.9355 fax • journals@asmusa.org Print ISSN: 0270-7306 Online ISSN: 1098-5549 Copyright © 2014 by the American Society for Microbiology.   For an alternate route to MCB .asm.org, visit: MCB       
    Subject(s): Alleles ; Base Sequence ; Chromosomes, Fungal - metabolism ; Crossing Over, Genetic ; DNA Breaks, Double-Stranded ; DNA Repair ; Genetic Markers ; Loss of Heterozygosity - genetics ; Models, Genetic ; Molecular Sequence Data ; Multiprotein Complexes - metabolism ; Mutation - genetics ; Phylogeny ; Rad51 Recombinase - metabolism ; Recombination, Genetic ; Schizosaccharomyces - cytology ; Schizosaccharomyces - genetics ; Schizosaccharomyces pombe ; Schizosaccharomyces pombe Proteins - metabolism ; Telomere - metabolism ; Translocation, Genetic
    ISSN: 0270-7306
    E-ISSN: 1098-5549
    Source: HighWire Press (Free Journals)
    Source: Hellenic Academic Libraries Link
    Source: PubMed Central
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  • 9
    Language: English
    In: Efficacy and mechanism evaluation, 2021-11, Vol.8 (20), p.1-106
    Description: Background The Efficacy and Mechanism Evaluation (EME) programme – a Medical Research Council (MRC) and National Institute for Health Research (NIHR) partnership – funds trials that evaluate the efficacy of interventions with the potential to promote health and studies that improve our understanding of the mechanisms of underlying diseases and their treatments. Objective To conduct an independent review of the EME programme’s impact and identify opportunities for future improvement. Design A mixed-methods approach, including desk research, an analysis of secondary data, stakeholder consultation and the development of impact case studies. Participants Chief investigators of EME awards, unfunded applicants to the EME programme and key opinion leaders relevant to the programme and research ecosystem. Interventions No interventions were tested, as this was a retrospective programme evaluation. Main outcome measures The evaluation was guided by a set of 15 evaluation questions. Results The EME programme bridges the gap between proof-of-concept and effectiveness studies that are located among other MRC and NIHR schemes and grants from charities in the funding landscape. Mechanistic studies alongside EME trials add value by lending confidence to trial findings and providing insights into the underlying biology. Between 2009 and September 2018, £175.7M in funding was approved for 145 EME projects. EME programme-funded research has started to deliver value to the NHS and patients by improving treatments and providing more efficient use of resources. Of the 43 completed trials, 14% (n = 6) showed that the intervention had a positive effect, whereas 74% (n = 32) of trials did not. The remaining five (12%) trials were unable to recruit participants or did not proceed to the full-trial stage. Seven projects (i.e. 16% of completed trials) have informed clinical guidelines or regulatory approval decisions and another eight projects have the potential to do so in the future, given the nature of their findings. Projects in the EME programme portfolio address a range of UK health needs and government priority areas, but they do not fully align with the level of health needs present. Commissioned calls for applications steer applicants. However, many commissioned calls do not lead to funded awards, and a better understanding of the underlying reasons for this would enable targeted supported to address key health needs. The majority of EME projects investigate existing interventions of limited commercial interest, focusing on repurposing (67/136, 49%) and informing current practice (23/136, 17%). Although there is little evidence of wider economic impact from commercial benefits, the EME programme is important in funding research in which industry is unlikely to invest. Stronger co-ordination with other funders, such as charities, could lead to synergies, enhancing the potential for health impact and influence on other funders’ agendas. The main challenges identified for EME projects were ‘complex and slow contracting processes’ (35/46, 76%), ‘setting up of study sites’ (30/46, 65%) and patient recruitment (28/46, 61%). Enablers of research included a clinical research fellow position on the project and support from Clinical Research Networks and Biomedical Research Centres. Nearly all of the chief investigators consulted had engaged in patient and public involvement at some project stage, and a lack of patient and public involvement did not emerge as a barrier to research or impact. Research ideas stemming from patients were, however, over-represented among unfunded applications, but the reason for this is unclear. Limitations Only about one-third of all studies had been completed or had published their main findings, necessitating a purposive, rather than representative, sampling of the portfolio. The COVID-19 outbreak cut short the programme of interviews, limiting the depth to which some evaluation questions could be explored. Several data sources were based on self-reporting by chief investigators; whereas key self-reported aspects were verified through desk research, this was not possible for all findings. Conclusions The EME programme plays an important role in the UK research funding landscape and has started to deliver value to the NHS and patients. Based on the evidence gathered, seven recommendations were developed to enhance the EME programme’s health and economic impact and address challenges encountered by chief investigators in implementing research projects. Funding This project was funded by the EME programme, a MRC and NIHR partnership. This will be published in full in Efficacy and Mechanism Evaluation; Vol. 8, No. 20. See the NIHR Journals Library website for further project information.
    Subject(s): barriers ; eme programme ; enablers ; evaluation ; health needs ; impact ; outcome ; research funding
    ISSN: 2050-4365
    E-ISSN: 2050-4373
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
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  • 10
    Language: English
    In: Applied and Environmental Microbiology, 2006-01-01, Vol.72 (1), p.953-955
    Description: Classifications Services AEM Citing Articles Google Scholar PubMed Related Content Social Bookmarking CiteULike Delicious Digg Facebook Google+ Mendeley Reddit StumbleUpon Twitter current issue Spotlights in the Current Issue AEM About AEM Subscribers Authors Reviewers Advertisers Inquiries from the Press Permissions & Commercial Reprints ASM Journals Public Access Policy AEM RSS Feeds 1752 N Street N.W. • Washington DC 20036 202.737.3600 • 202.942.9355 fax • journals@asmusa.org Print ISSN: 0099-2240 Online ISSN: 1098-5336 Copyright © 2014 by the American Society for Microbiology.   For an alternate route to AEM .asm.org, visit: AEM       
    Subject(s): Analysis ; Aspergillus ; Aspergillus niger ; Aspergillus niger - genetics ; Aspergillus niger - metabolism ; Biological and medical sciences ; Biotechnology ; Fundamental and applied biological sciences. Psychology ; Fungal Proteins - genetics ; Fungal Proteins - metabolism ; Gene Expression Regulation, Fungal ; Genetic aspects ; HSP70 Heat-Shock Proteins - genetics ; HSP70 Heat-Shock Proteins - metabolism ; Membrane proteins ; Membrane Proteins - genetics ; Membrane Proteins - metabolism ; Membranes ; Microbiology ; Mycology ; NADH, NADPH Oxidoreductases - genetics ; NADH, NADPH Oxidoreductases - metabolism ; Oxygenases - genetics ; Oxygenases - metabolism ; Polymerase chain reaction ; Properties ; Proteins ; Ribonucleic acid ; RNA ; RNA, Messenger - genetics ; RNA, Messenger - metabolism ; Transcription Factors - genetics ; Transcription Factors - metabolism
    ISSN: 0099-2240
    E-ISSN: 1098-5336
    Source: HighWire Press (Free Journals)
    Source: Hellenic Academic Libraries Link
    Source: PubMed Central
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