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  • 1
    Language: English
    In: Nature communications, 2014-06-09, Vol.5 (1), p.4091-4091
    Description: DNA double-strand break (DSB) repair is a highly regulated process performed predominantly by non-homologous end joining (NHEJ) or homologous recombination (HR) pathways. How these pathways are coordinated in the context of chromatin is unclear. Here we uncover a role for histone H3K36 modification in regulating DSB repair pathway choice in fission yeast. We find Set2-dependent H3K36 methylation reduces chromatin accessibility, reduces resection and promotes NHEJ, while antagonistic Gcn5-dependent H3K36 acetylation increases chromatin accessibility, increases resection and promotes HR. Accordingly, loss of Set2 increases H3K36Ac, chromatin accessibility and resection, while Gcn5 loss results in the opposite phenotypes following DSB induction. Further, H3K36 modification is cell cycle regulated with Set2-dependent H3K36 methylation peaking in G1 when NHEJ occurs, while Gcn5-dependent H3K36 acetylation peaks in S/G2 when HR prevails. These findings support an H3K36 chromatin switch in regulating DSB repair pathway choice.
    Subject(s): Acetylation ; Acetyltransferases - metabolism ; Chromatin - metabolism ; DNA End-Joining Repair ; DNA Repair ; DNA, Fungal - metabolism ; Histone-Lysine N-Methyltransferase - metabolism ; Histones - metabolism ; Methylation ; Recombinational DNA Repair ; Schizosaccharomyces - genetics ; Schizosaccharomyces - metabolism ; Schizosaccharomyces pombe Proteins - metabolism
    ISSN: 2041-1723
    E-ISSN: 2041-1723
    Source: Nature Open Access
    Source: PubMed Central
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
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  • 2
    Language: English
    In: The Journal of biological chemistry, 2019-10-04, Vol.294 (40), p.14686-14703
    Description: CTP synthase (CTPS) has been demonstrated to form evolutionarily-conserved filamentous structures termed cytoophidia whose exact cellular functions remain unclear, but they may play a role in intracellular compartmentalization. We have previously shown that the mammalian target of rapamycin complex 1 (mTORC1)–S6K1 pathway mediates cytoophidium assembly in mammalian cells. Here, using the fission yeast Schizosaccharomyces pombe as a model of a unicellular eukaryote, we demonstrate that the target of rapamycin (TOR)-signaling pathway regulates cytoophidium formation (from the S. pombe CTPS ortholog Cts1) also in S. pombe. Conducting a systematic analysis of all viable single TOR subunit–knockout mutants and of several major downstream effector proteins, we found that Cts1 cytoophidia are significantly shortened and often dissociate when TOR is defective. We also found that the activities of the downstream effector kinases of the TORC1 pathway, Sck1, Sck2, and Psk1 S6, as well as of the S6K/AGC kinase Gad8, the major downstream effector kinase of the TORC2 pathway, are necessary for proper cytoophidium filament formation. Interestingly, we observed that the Crf1 transcriptional corepressor for ribosomal genes is a strong effector of Cts1 filamentation. Our findings connect TOR signaling, a major pathway required for cell growth, with the compartmentalization of the essential nucleotide synthesis enzyme CTPS, and we uncover differences in the regulation of its filamentation among higher multicellular and unicellular eukaryotic systems.
    Subject(s): Biochemistry & Molecular Biology ; Carbon-Nitrogen Ligases - chemistry ; Carbon-Nitrogen Ligases - genetics ; Cell Biology ; Cell Compartmentation - genetics ; CTP synthase ; cytoophidium ; Cytoplasm - genetics ; fission yeast ; Gene Knockout Techniques ; kinase signaling ; Life Sciences & Biomedicine ; Mechanistic Target of Rapamycin Complex 1 - genetics ; Mechanistic Target of Rapamycin Complex 2 - genetics ; metabolic regulation ; nucleotide ; Phosphorylation - genetics ; protein filamentation ; Protein-Serine-Threonine Kinases - chemistry ; Protein-Serine-Threonine Kinases - genetics ; pyrimidine ; Receptors, Corticotropin-Releasing Hormone - chemistry ; Receptors, Corticotropin-Releasing Hormone - genetics ; Schizosaccharomyces - genetics ; Schizosaccharomyces pombe ; Schizosaccharomyces pombe Proteins - chemistry ; Schizosaccharomyces pombe Proteins - genetics ; Science & Technology ; signal transduction ; Signal Transduction - genetics ; subcellular organelle ; target of rapamycin (TOR) ; TOR complex (TORC) ; Transcription Factors - chemistry ; Transcription Factors - genetics ; yeast ; yeast genetics
    ISSN: 0021-9258
    E-ISSN: 1083-351X
    Source: HighWire Press (Free Journals)
    Source: Web of Science - Science Citation Index Expanded - 2019〈img src="http://exlibris-pub.s3.amazonaws.com/fromwos-v2.jpg" /〉
    Source: PubMed Central
    Source: Alma/SFX Local Collection
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
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  • 3
    Language: English
    In: Chromosoma, 2019-05-09, Vol.128 (3), p.249-265
    Description: We investigated the meiotic role of Srs2, a multi-functional DNA helicase/translocase that destabilises Rad51-DNA filaments and is thought to regulate strand invasion and prevent hyper-recombination during the mitotic cell cycle. We find that Srs2 activity is required for normal meiotic progression and spore viability. A significant fraction of srs2 mutant cells progress through both meiotic divisions without separating the bulk of their chromatin, although in such cells sister centromeres often separate. Undivided nuclei contain aggregates of Rad51 colocalised with the ssDNA-binding protein RPA, suggesting the presence of persistent single-strand DNA. Rad51 aggregate formation requires Spo11-induced DSBs, Rad51 strand-invasion activity and progression past the pachytene stage of meiosis, but not the DSB end-resection or the bias towards interhomologue strand invasion characteristic of normal meiosis. srs2 mutants also display altered meiotic recombination intermediate metabolism, revealed by defects in the formation of stable joint molecules. We suggest that Srs2, by limiting Rad51 accumulation on DNA, prevents the formation of aberrant recombination intermediates that otherwise would persist and interfere with normal chromosome segregation and nuclear division.
    Subject(s): Animal Genetics and Genomics ; Biochemistry ; Biochemistry & Molecular Biology ; Biomedical and Life Sciences ; Budding yeast ; Cell Biology ; Cell cycle ; Centromeres ; Chromatin ; Deoxyribonucleic acid ; Developmental Biology ; DNA ; DNA helicase ; Eukaryotic Microbiology ; Filaments ; general ; Genetics & Heredity ; Human Genetics ; Intermediates ; Life Sciences ; Life Sciences & Biomedicine ; Meiosis ; Metabolism ; Nuclear division ; Original ; Original Article ; Pachytene ; Rad51 ; Recombination ; Science & Technology ; Srs2 helicase ; Translocase ; Yeast
    ISSN: 0009-5915
    E-ISSN: 1432-0886
    Source: Web of Science - Science Citation Index Expanded - 2019〈img src="http://exlibris-pub.s3.amazonaws.com/fromwos-v2.jpg" /〉
    Source: Alma/SFX Local Collection
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  • 4
    Language: English
    In: Biology open, 2014-10-31, Vol.3 (11), p.1092-1097
    Description: A general view is that Schizosaccharomyces pombe undergoes symmetric cell division with two daughter cells inheriting equal shares of the content from the mother cell. Here we show that CTP synthase, a metabolic enzyme responsible for the de novo synthesis of the nucleotide CTP, can form filamentous cytoophidia in the cytoplasm and nucleus of S. pombe cells. Surprisingly, we observe that both cytoplasmic and nuclear cytoophidia are asymmetrically inherited during cell division. Our time-lapse studies suggest that cytoophidia are dynamic. Once the mother cell divides, the cytoplasmic and nuclear cytoophidia independently partition into one of the two daughter cells. Although the two daughter cells differ from one another morphologically, they possess similar chances of inheriting the cytoplasmic cytoophidium from the mother cell, suggesting that the partition of cytoophidium is a stochastic process. Our findings on asymmetric inheritance of cytoophidia in S. pombe offer an exciting opportunity to study the inheritance of metabolic enzymes in a well-studied model system.
    Subject(s): Asymmetric inheritance ; CTP synthase ; Cytoophidium ; Intracellular compartmentation ; Schizosaccharomyces pombe
    ISSN: 2046-6390
    E-ISSN: 2046-6390
    Source: PubMed Central
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  • 5
    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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  • 6
    Language: English
    In: Nucleic acids research, 2014-05-01, Vol.42 (9), p.5644-5656
    Description: DNA double-strand breaks (DSBs) can cause chromosomal rearrangements and extensive loss of heterozygosity (LOH), hallmarks of cancer cells. Yet, how such events are normally suppressed is unclear. Here we identify roles for the DNA damage checkpoint pathway in facilitating homologous recombination (HR) repair and suppressing extensive LOH and chromosomal rearrangements in response to a DSB. Accordingly, deletion of Rad3ATR, Rad26ATRIP, Crb253BP1 or Cdc25 overexpression leads to reduced HR and increased break-induced chromosome loss and rearrangements. We find the DNA damage checkpoint pathway facilitates HR, in part, by promoting break-induced Cdt2-dependent nucleotide synthesis. We also identify additional roles for Rad17, the 9-1-1 complex and Chk1 activation in facilitating break-induced extensive resection and chromosome loss, thereby suppressing extensive LOH. Loss of Rad17 or the 9-1-1 complex results in a striking increase in break-induced isochromosome formation and very low levels of chromosome loss, suggesting the 9-1-1 complex acts as a nuclease processivity factor to facilitate extensive resection. Further, our data suggest redundant roles for Rad3ATR and Exo1 in facilitating extensive resection. We propose that the DNA damage checkpoint pathway coordinates resection and nucleotide synthesis, thereby promoting efficient HR repair and genome stability.
    Subject(s): Cell Cycle Checkpoints ; Checkpoint Kinase 2 - metabolism ; Chromosomes, Fungal - genetics ; Comparative Genomic Hybridization ; DNA Breaks, Double-Stranded ; DNA Cleavage ; Exodeoxyribonucleases - metabolism ; Genome Integrity, Repair and ; Genome, Fungal ; Genomic Instability ; Loss of Heterozygosity ; Nucleotides - biosynthesis ; Recombinational DNA Repair ; Schizosaccharomyces - genetics ; Schizosaccharomyces - metabolism ; Schizosaccharomyces pombe ; Schizosaccharomyces pombe Proteins - metabolism
    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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  • 7
    Language: English
    Description: Meiosis is a cell division in which one diploid parent cell produces four haploid daughter cells. Accurate alignment and segregation of homologous chromosomes during metaphase is critical for a successful meiotic division and viable gametes. Three concomitant events are required for a successful meiotic division: chromosome pairing, synapsis and recombination. Recombination is initiated by programmed induction of DNA double-strand breaks (DSBs). Interchromosomal repair of meiotic DSBs can form a crossover leading to genetic diversity by modifying linkage groups. Crossovers also tether the homologous chromosomes and help resist the tension of the first meiotic spindle. Controlled recombination is required for a successful meiotic division and segregation, however, recombination has to be tightly regulated. This work investigates the roles of Te11,Rad6 and Srs2 during meiotic homologous DSB repair. Tel1 is protein kinase required for initiating a signalling cascade in response to many forms of DNA damage. Tel1 has also been proven to function during meiosis and has been shown in some conditions to initiate a signalling cascade after the initiation of meiotic DSBs. In this work Tel1 is shown to influence the early stages of DSB repair during meiosis, however this is not in response to the formation of Spo11-DSB. Recombination ensures genetic variation and correct homologue alignment during meiosis I therefore is extremely important and tightly controlled. Srs2 is known to be a negative regulator of recombination and is important for normal sporeulation and viability in yeast. Analysis of an experimental site specific DSB (made by VDE) and at natural Spo11-DSBs indicates that in the absence of Srs2 the rate of repair can be increased at Spo11-DSBs and decreased at the VDE-DSB. One potential role for Srs2 during meiosis is to dismantle recombination intermediates formed between the sister chromatids. Rad6 is required for wild type amounts of Spo11-DSB formation. This work investigated the VDE-DSB repair in the absence of Rad6, and discovered that Rad6 has a role in the initiation of repair. Rad6 ubiquitinates histone H2B, and further analyses suggest that this modification is required for repair at the VDEDSB. Each of the genes studied is required for wild type repair of VDE-DSBs and Spo11-DSBS, even though they come from widely different functional groups. This illustrates the diversity of cellular pathways controlling the initiation and regulation of meiotic recombination.
    Source: ProQuest Dissertations & Theses Global
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  • 8
    Language: English
    In: Health technology assessment (Winchester, England), 2017-04, Vol.21 (17), p.1-122
    Description: Planned neck dissection (ND) after radical chemoradiotherapy (CRT) for locally advanced nodal metastases in patients with head and neck squamous cell carcinoma (HNSCC) remains controversial. Thirty per cent of ND specimens show histological evidence of tumour. Consequently, a significant proportion of clinicians still practise planned ND. Fludeoxyglucose positron emission tomography (PET)-computerised tomography (CT) scanning demonstrated high negative predictive values for persistent nodal disease, providing a possible alternative paradigm to ND. Evidence is sparse and drawn mainly from retrospective single-institution studies, illustrating the need for a prospective randomised controlled trial. To determine the efficacy and cost-effectiveness of PET-CT-guided surveillance, compared with planned ND, in a multicentre, prospective, randomised setting. A pragmatic randomised non-inferiority trial comparing PET-CT-guided watch-and-wait policy with the current planned ND policy in HNSCC patients with locally advanced nodal metastases and treated with radical CRT. Patients were randomised in a 1 : 1 ratio. Primary outcomes were overall survival (OS) and cost-effectiveness [incremental cost per incremental quality-adjusted life-year (QALY)]. Cost-effectiveness was assessed over the trial period using individual patient data, and over a lifetime horizon using a decision-analytic model. Secondary outcomes were recurrence in the neck, complication rates and quality of life. The recruitment of 560 patients was planned to detect non-inferior OS in the intervention arm with a 90% power and a type I error of 5%, with non-inferiority defined as having a hazard ratio (HR) of no higher than 1.50. An intention-to-treat analysis was performed by Cox's proportional hazards model. Thirty-seven head and neck cancer-treating centres (43 NHS hospitals) throughout the UK. Patients with locally advanced nodal metastases of oropharynx, hypopharynx, larynx, oral or occult HNSCC receiving CRT and fit for ND were recruited. Patients randomised to planned ND before or after CRT (control), or CRT followed by fludeoxyglucose PET-CT 10-12 weeks post CRT with ND only if PET-CT showed incomplete or equivocal response of nodal disease (intervention). Balanced by centre, planned ND timing, CRT schedule, disease site and the tumour, node, metastasis stage. In total, 564 patients were recruited (ND arm,  = 282; and surveillance arm,  = 282; 17% N2a, 61% N2b, 18% N2c and 3% N3). Eighty-four per cent had oropharyngeal cancer. Seventy-five per cent of tested cases were p16 positive. The median time to follow-up was 36 months. The HR for OS was 0.92 [95% confidence interval (CI) 0.65 to 1.32], indicating non-inferiority. The upper limit of the non-inferiority HR margin of 1.50, which was informed by patient advisors to the project, lies at the 99.6 percentile of this estimate (  = 0.004). There were no differences in this result by p16 status. There were 54 NDs performed in the surveillance arm, with 22 surgical complications, and 221 NDs in the ND arm, with 85 complications. Quality-of-life scores were slightly better in the surveillance arm. Compared with planned ND, PET-CT surveillance produced an incremental net health benefit of 0.16 QALYs (95% CI 0.03 to 0.28 QALYs) over the trial period and 0.21 QALYs (95% CI -0.41 to 0.85 QALYs) over the modelled lifetime horizon. Pragmatic randomised controlled trial with a 36-month median follow-up. PET-CT-guided active surveillance showed similar survival outcomes to ND but resulted in considerably fewer NDs, fewer complications and lower costs, supporting its use in routine practice. PET-CT surveillance is cost-effective in the short term, and long-term cost-effectiveness could be addressed in future work. Current Controlled Trials ISRCTN13735240. This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in ; Vol. 21, No. 17. See the NIHR Journals Library website for further project information.
    Subject(s): Carcinoma, Squamous Cell - diagnosis ; Carcinoma, Squamous Cell - surgery ; Carcinoma, Squamous Cell - therapy ; Chemoradiotherapy ; Cost-Benefit Analysis ; Female ; Head and Neck Neoplasms - diagnosis ; Head and Neck Neoplasms - surgery ; Head and Neck Neoplasms - therapy ; head and neck squamous cell carcinoma ; Humans ; locally advanced nodal metastases ; Male ; Middle Aged ; Neck Dissection ; Positron Emission Tomography Computed Tomography ; positron emission tomography–computerised tomography ; Quality-Adjusted Life Years ; randomised non-inferiority trial ; Squamous Cell Carcinoma of Head and Neck ; Survival Rate ; Technology Assessment, Biomedical ; United Kingdom ; Watchful Waiting - methods
    ISSN: 1366-5278
    E-ISSN: 2046-4924
    Source: Alma/SFX Local Collection
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
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  • 9
    Language: English
    In: The New England journal of medicine, 2016-04-14, Vol.374 (15), p.1444-1454
    Description: Among patients who received chemotherapy for advanced head and neck cancer, 2-year overall survival was 81.5% in the group assigned to immediate radical neck dissection and 84.9% in the group assigned to positron-emission tomographic–computed tomographic surveillance. Chemoradiotherapy has become a mainstay of primary treatment in patients with squamous-cell carcinoma of the head and neck. However, there are wide variations in the management of advanced nodal disease (stage N2 or N3) in these patients because of the lack of prospective, randomized, controlled trials. 1 , 2 Retrospective studies showed persistent disease on histopathological examination of nodes in up to 40% of patients who underwent neck dissection after chemoradiotherapy 3 and some evidence of a significant survival advantage associated with planned neck dissection. 4 , 5 However, owing to improvements in cross-sectional imaging, consistently low rates of recurrence (〈10%) have been reported among . . .
    Subject(s): Abridged Index Medicus ; Cancer ; Cancer therapies ; Carcinoma, Squamous Cell - diagnosis ; Carcinoma, Squamous Cell - surgery ; Carcinoma, Squamous Cell - therapy ; Care and treatment ; Chemoradiotherapy ; Chemotherapy ; Clinical trials ; Computed tomography ; Diagnosis ; Dissection ; Female ; Follow-Up Studies ; Head & neck cancer ; Head and neck cancer ; Head and Neck Neoplasms - diagnosis ; Head and Neck Neoplasms - surgery ; Head and Neck Neoplasms - therapy ; Human papillomavirus ; Humans ; Intention to Treat Analysis ; Kaplan-Meier Estimate ; Lymphatic Metastasis - diagnosis ; Male ; Medical care, Cost of ; Middle Aged ; Neck ; Neck Dissection ; Neoplasm Recurrence, Local ; Neoplasm Staging ; Oropharyngeal cancer ; p16 Protein ; Patients ; PET imaging ; Positron emission tomography ; Prospective Studies ; Quality of Life ; Surgery ; Survival Rate ; Tomography ; Tomography, X-Ray Computed ; Usage
    ISSN: 0028-4793
    E-ISSN: 1533-4406
    Source: Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals
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  • 10
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