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  • 1
    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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  • 2
    Language: English
    In: EMBO reports, 2013-08, Vol.14 (8), p.711-717
    Description: We have applied chromatin sequencing technology to the euryarchaeon Thermococcus kodakarensis, which is known to possess histone‐like proteins. We detect positioned chromatin particles of variable sizes associated with lengths of DNA differing as multiples of 30 bp (ranging from 30 bp to 〉450 bp) consistent with formation from dynamic polymers of the archaeal histone dimer. T. kodakarensis chromatin particles have distinctive underlying DNA sequence suggesting a genomic particle‐positioning code and are excluded from gene‐regulatory DNA suggesting a functional organization. Beads‐on‐a‐string chromatin is therefore conserved between eukaryotes and archaea but can derive from deployment of histone‐fold proteins in a variety of multimeric forms. Chromatin‐sequencing reveals an archaeal histone‐protein based chromatin architecture, in which the beads‐on‐a‐string vary in size and associate with DNA lengths of 30bp or multiples thereof.
    Subject(s): Archaea ; Archaeal Proteins - chemistry ; Archaeal Proteins - genetics ; Archaeal Proteins - metabolism ; Chromatin ; chromatin-seq ; Deoxyribonucleic acid ; DNA ; DNA, Archaeal - chemistry ; DNA, Archaeal - genetics ; DNA, Archaeal - metabolism ; Genome, Archaeal ; histone ; Histones - chemistry ; Histones - genetics ; Histones - metabolism ; Nucleic Acid Conformation ; nucleosome ; Nucleosomes - chemistry ; Nucleosomes - genetics ; Nucleosomes - metabolism ; Protein Folding ; Protein Multimerization ; Proteins ; Scientific Reports ; Thermococcus ; Thermococcus - genetics ; Thermococcus - metabolism
    ISSN: 1469-221X
    E-ISSN: 1469-3178
    Source: HighWire Press (Free Journals)
    Source: PubMed Central
    Source: Get It Now
    Source: Wiley-Blackwell Full Collection 2014
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  • 3
    Language: English
    In: Journal of cell science, 2019-03-25, Vol.132 (6)
    Description: Replication stress is a common feature of cancer cells, and thus a potentially important therapeutic target. Here, we show that cyclin-dependent kinase (CDK)-induced replication stress, resulting from Wee1 inactivation, is synthetic lethal with mutations disrupting dNTP homeostasis in fission yeast. Wee1 inactivation leads to increased dNTP demand and replication stress through CDK-induced firing of dormant replication origins. Subsequent dNTP depletion leads to inefficient DNA replication, DNA damage and to genome instability. Cells respond to this replication stress by increasing dNTP supply through histone methyltransferase Set2-dependent MBF-induced expression of Cdc22, the catalytic subunit of ribonucleotide reductase (RNR). Disrupting dNTP synthesis following Wee1 inactivation, through abrogating Set2-dependent H3K36 tri-methylation or DNA integrity checkpoint inactivation results in critically low dNTP levels, replication collapse and cell death, which can be rescued by increasing dNTP levels. These findings support a 'dNTP supply and demand' model in which maintaining dNTP homeostasis is essential to prevent replication catastrophe in response to CDK-induced replication stress.
    Subject(s): Cell Cycle Checkpoints ; Cell Cycle Proteins - metabolism ; Cyclin-Dependent Kinases - metabolism ; DNA Damage ; DNA Replication ; Histone Code ; Histone-Lysine N-Methyltransferase - metabolism ; Histones - metabolism ; Homeostasis ; Methylation ; Nucleotides - metabolism ; Protein-Tyrosine Kinases - metabolism ; Schizosaccharomyces - metabolism ; Schizosaccharomyces pombe Proteins - metabolism ; Synthetic Lethal Mutations ; Transcription Factors - metabolism
    E-ISSN: 1477-9137
    Source: HighWire Press (Free Journals)
    Source: Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals
    Source: Company of Biologists
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  • 4
    Language: English
    In: Journal of cell science, 2019-03-01, Vol.132 (6)
    Description: Replication stress is a common feature of cancer cells, and thus a potentially important therapeutic target. Here, we show that cyclin-dependent kinase (CDK)-induced replication stress, resulting from Weel inactivation, is synthetic lethal with mutations disrupting dNTP homeostasis in fission yeast. Weel inactivation leads to increased dNTP demand and replication stress through CDK-induced firing of dormant replication origins. Subsequent dNTP depletion leads to inefficient DNA replication, DNA damage and to genome instability. Cells respond to this replication stress by increasing dNTP supply through histone methyltransferase Set2-dependent MBF-induced expression of Cdc22, the catalytic subunit of ribonucleotide reductase (RNR). Disrupting dNTP synthesis following Wee 1 inactivation, through abrogating Set2-dependent H3K36 tri-methylation or DNA integrity checkpoint inactivation results in critically low dNTP levels, replication collapse and cell death, which can be rescued by increasing dNTP levels. These findings support a ANTP supply and demand' model in which maintaining dNTP homeostasis is essential to prevent replication catastrophe in response to CDK-induced replication stress.
    Subject(s): CDK ; Cell Biology ; Histone H3K36 modification ; Life Sciences & Biomedicine ; MBF ; Schizosaccharomyces pombe ; Science & Technology ; Set2 ; Synthetic lethality ; Wee1
    ISSN: 0021-9533
    E-ISSN: 1477-9137
    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: Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals
    Source: Company of Biologists
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  • 5
    Language: English
    In: Genes & development, 2012-12-01, Vol.26 (23), p.2590-2603
    Description: The INO80 chromatin remodeling complex functions in transcriptional regulation, DNA repair, and replication. Here we uncover a novel role for INO80 in regulating chromosome segregation. First, we show that the conserved Ies6 subunit is critical for INO80 function in vivo. Strikingly, we found that loss of either Ies6 or the Ino80 catalytic subunit results in rapid increase in ploidy. One route to polyploidy is through chromosome missegregation due to aberrant centromere structure, and we found that loss of either Ies6 or Ino80 leads to defective chromosome segregation. Importantly, we show that chromatin structure flanking centromeres is altered in cells lacking these subunits and that these alterations occur not in the Cse4-containing centromeric nucleosome, but in pericentric chromatin. We provide evidence that these effects are mediated through misincorporation of H2A.Z, and these findings indicate that H2A.Z-containing pericentric chromatin, as in higher eukaryotes with regional centromeres, is important for centromere function in budding yeast. These data reveal an important additional mechanism by which INO80 maintains genome stability.
    Subject(s): centromere ; Centromere - chemistry ; Centromere - metabolism ; Chromatin ; Chromatin - chemistry ; Chromatin Assembly and Disassembly ; Chromosomal Proteins, Non-Histone - genetics ; Chromosomal Proteins, Non-Histone - metabolism ; Chromosome Segregation ; Crossing over (Genetics) ; Cytogenetics ; DNA Damage ; Gene Expression Regulation, Fungal ; Genetic aspects ; Genetic regulation ; H2A.Z ; Histones - genetics ; Ies6 ; INO80 ; Mutation ; Polyploidy ; Research Paper ; Saccharomyces cerevisiae - genetics ; Saccharomyces cerevisiae - metabolism ; Saccharomyces cerevisiae Proteins - genetics ; Saccharomyces cerevisiae Proteins - metabolism
    ISSN: 0890-9369
    E-ISSN: 1549-5477
    Source: HighWire Press (Free Journals)
    Source: Cold Spring Harbor Laboratory Press
    Source: Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals
    Source: PubMed Central
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  • 6
    Language: English
    In: PloS one, 2012, Vol.7 (2), p.e32016-e32016
    Description: The RSC chromatin remodeling complex has been implicated in contributing to DNA double-strand break (DSB) repair in a number of studies. Both survival and levels of H2A phosphorylation in response to damage are reduced in the absence of RSC. Importantly, there is evidence for two isoforms of this complex, defined by the presence of either Rsc1 or Rsc2. Here, we investigated whether the two isoforms of RSC provide distinct contributions to DNA damage responses. First, we established that the two isoforms of RSC differ in the presence of Rsc1 or Rsc2 but otherwise have the same subunit composition. We found that both rsc1 and rsc2 mutant strains have intact DNA damage-induced checkpoint activity and transcriptional induction. In addition, both strains show reduced non-homologous end joining activity and have a similar spectrum of DSB repair junctions, suggesting perhaps that the two complexes provide the same functions. However, the hypersensitivity of a rsc1 strain cannot be complemented with an extra copy of RSC2, and likewise, the hypersensitivity of the rsc2 strain remains unchanged when an additional copy of RSC1 is present, indicating that the two proteins are unable to functionally compensate for one another in DNA damage responses. Rsc1, but not Rsc2, is required for nucleosome sliding flanking a DNA DSB. Interestingly, while swapping the domains from Rsc1 into the Rsc2 protein does not compromise hypersensitivity to DNA damage suggesting they are functionally interchangeable, the BAH domain from Rsc1 confers upon Rsc2 the ability to remodel chromatin at a DNA break. These data demonstrate that, despite the similarity between Rsc1 and Rsc2, the two different isoforms of RSC provide distinct functions in DNA damage responses, and that at least part of the functional specificity is dictated by the BAH domains.
    Subject(s): Biology ; Breast cancer ; Chromatin ; Chromatin Assembly and Disassembly ; Chromatin remodeling ; Chromosomal Proteins, Non-Histone - physiology ; Cloning ; Councils ; Deoxyribonucleic acid ; DNA ; DNA Damage ; DNA Repair ; Double-strand break repair ; Fungal Proteins ; Genes ; Genetic transcription ; Genomes ; Homology ; Hypersensitivity ; Isoforms ; Medical research ; Mutation ; Non-homologous end joining ; Phosphorylation ; Protein Isoforms ; Protein Structure, Tertiary ; Proteins ; Repair ; Saccharomyces cerevisiae - genetics ; Saccharomyces cerevisiae - physiology ; Saccharomyces cerevisiae Proteins - physiology ; Subunit structure ; Transcription ; Yeast
    ISSN: 1932-6203
    E-ISSN: 1932-6203
    Source: Academic Search Ultimate
    Source: PubMed Central
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
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  • 7
    Language: English
    In: Clinical cancer research, 2021-02-15, Vol.27 (4), p.937-962
    Description: Preclinical models of cancer have demonstrated enhanced efficacy of cell-cycle checkpoint kinase inhibitors when used in combination with genotoxic agents. This combination therapy is predicted to be exquisitely toxic to cells with a deficient G -S checkpoint or cells with a genetic predisposition leading to intrinsic DNA replication stress, as these cancer cells become fully dependent on the intra-S and G -M checkpoints for DNA repair and cellular survival. Therefore, abolishing remaining cell-cycle checkpoints after damage leads to increased cell death in a tumor cell-specific fashion. However, the preclinical success of these drug combinations is not consistently replicated in clinical trials. Here, we provide a perspective on the translation of preclinical studies into rationally designed clinical studies. We will discuss successes and failures of current treatment combinations and drug regimens and provide a detailed overview of all clinical trials using ATR, CHK1, or WEE1 inhibitors in combination with genotoxic agents. This highlights the need for revised patient stratification and the use of appropriate pharmacodynamic biomarkers to improve the success rate of clinical trials.
    Subject(s): Antineoplastic Combined Chemotherapy Protocols - pharmacology ; Antineoplastic Combined Chemotherapy Protocols - therapeutic use ; Ataxia Telangiectasia Mutated Proteins - antagonists & inhibitors ; Cell Cycle Proteins - antagonists & inhibitors ; Checkpoint Kinase 1 - antagonists & inhibitors ; Chemoradiotherapy - methods ; Clinical Trials as Topic ; DNA Damage - drug effects ; DNA Damage - radiation effects ; Drug Screening Assays, Antitumor ; Humans ; Neoplasms - genetics ; Neoplasms - mortality ; Neoplasms - pathology ; Neoplasms - therapy ; Progression-Free Survival ; Protein Kinase Inhibitors - pharmacology ; Protein Kinase Inhibitors - therapeutic use ; Protein-Tyrosine Kinases - antagonists & inhibitors
    ISSN: 1078-0432
    E-ISSN: 1557-3265
    Source: HighWire Press (Free Journals)
    Source: Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals
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  • 8
    Language: English
    Description: Replication stress is a common feature of cancer cells, and thus a potentially important therapeutic target. Here we show that CDK-induced replication stress is synthetic lethal with mutations disrupting dNTP homeostasis in fission yeast. Wee1 inactivation leads to increased dNTP demand and replication stress through CDK-induced firing of dormant replication origins. Subsequent dNTP depletion leads to inefficient DNA replication, DNA damage, and to genome instability. Cells respond to this replication stress by increasing dNTP supply through Set2-dependent MBF-induced expression of Cdc22, the catalytic subunit of ribonucleotide reductase (RNR). Disrupting dNTP synthesis following Wee1 inactivation, through abrogating Set2-dependent H3K36 tri-methylation or DNA integrity checkpoint inactivation results in critically low dNTP levels, replication collapse and cell death, which can be rescued by increasing dNTP levels. These findings support a ‘dNTP supply and demand’ model in which maintaining dNTP homeostasis is essential to prevent replication catastrophe in response to CDK-induced replication stress.
    ISSN: 0021-9533
    E-ISSN: 1477-9137
    Source: HighWire Press (Free Journals)
    Source: Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals
    Source: ROAR (University of East London Repository)
    Source: Company of Biologists
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  • 9
    Language: English
    Description: RSC is a member of the multi-subunit SWI/SNF family of ATPase-dependent chromatin remodellers and it is implicated in transcriptional regulation and DNA repair in Saccharomyces cerevisiae. The central ATPase subunit, Sth1, translocates nucleosomes in vitro and mutations in human RSC sub-unit orthologues are implicated in human disease. RSC is found in two isoforms, defined by the presence of either the Rsc1 or Rsc2 subunits, and these appear to confer distinct remodelling functions in different genomic contexts. At the MAT locus, Rsc1 and Rsc2 appear to mediate different forms of nucleosome positioning which are required for efficient mating type switching. Elsewhere in the genome, it has been suggested that RSC can create partially un-wrapped nucleosomes in order to facilitate transcription factor binding. This thesis uses indirect-end-label analysis and chromatin-sequencing technologies to dissect the chromatin remodelling functions of RSC and to determine the roles of Rsc1, Rsc2 and their subdomains. The work presented here suggests that four chromatin-remodelling outcomes arise from RSC activity. Firstly, RSC alters the positions of a tract of nucleosomes abutting HO endonuclease-induced double-strand DNA breaks both at MAT and non-MAT loci in a Rsc1-dependent manner. This activity can be transferred from Rsc1 to Rsc2 by swapping BAH domains. Secondly, RSC can aggregate nucleosomes into a large nuclease-resistant structure, termed an alphasome, in a Rsc2- and Rsc7-dependent manner. Thirdly, RSC positions nucleosomes at tRNA genes in a manner that requires both Rsc1 and Rsc2. Finally, chromatin particles consistent with previously described un-wound nucleosomes are confirmed to be present in specific promoter regions. Although Rsc1- and Rsc2- dependent subsets of these promoters could be identified, and associations with binding motifs for particular transcriptions factors were discovered, it was ultimately not possible to unambiguously define why some gene promoters depend on one RSC sub-unit rather than the other.
    Subject(s): Genetics
    Source: ProQuest Dissertations & Theses Global
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