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  • 1
    Language: English
    In: Genes, 2017-01-31, Vol.8 (2), p.57
    Description: A crucial factor in maintaining genome stability is establishing deoxynucleoside triphosphate (dNTP) levels within a range that is optimal for chromosomal replication. Since DNA replication is relevant to a wide range of other chromosomal activities, these may all be directly or indirectly affected when dNTP concentrations deviate from a physiologically normal range. The importance of understanding these consequences is relevant to genetic disorders that disturb dNTP levels, and strategies that inhibit dNTP synthesis in cancer chemotherapy and for treatment of other disorders. We review here how abnormal dNTP levels affect DNA replication and discuss the consequences for genome stability.
    Subject(s): Cell cycle ; Cyclin-dependent kinases ; DNA damage ; DNA polymerase ; dNTP ; Enzymes ; Genetic disorders ; genome instability ; Genomes ; Localization ; Mitochondrial DNA ; Oncology ; Phosphorylation ; proofreading ; Proteins ; replication fidelity ; Review ; Ribonucleotide reductase
    ISSN: 2073-4425
    E-ISSN: 2073-4425
    Source: PubMed Central
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
    Source: ProQuest Central
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  • 2
    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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  • 3
    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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  • 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: Cell reports (Cambridge), 2017-09-12, Vol.20 (11), p.2693-2705
    Description: Chromatin modification through histone H3 lysine 36 methylation by the SETD2 tumor suppressor plays a key role in maintaining genome stability. Here, we describe a role for Set2-dependent H3K36 methylation in facilitating DNA replication and the transcriptional responses to both replication stress and DNA damage through promoting MluI cell-cycle box (MCB) binding factor (MBF)-complex-dependent transcription in fission yeast. Set2 loss leads to reduced MBF-dependent ribonucleotide reductase (RNR) expression, reduced deoxyribonucleoside triphosphate (dNTP) synthesis, altered replication origin firing, and a checkpoint-dependent S-phase delay. Accordingly, prolonged S phase in the absence of Set2 is suppressed by increasing dNTP synthesis. Furthermore, H3K36 is di- and tri-methylated at these MBF gene promoters, and Set2 loss leads to reduced MBF binding and transcription in response to genotoxic stress. Together, these findings provide new insights into how H3K36 methylation facilitates DNA replication and promotes genotoxic stress responses in fission yeast. [Display omitted] •Set2 methyltransferase is required for efficient DNA replication•Set2 loss reduces dNTP synthesis and alters replication origin firing•Set2 promotes efficient MBF-dependent transcription•Increasing dNTP synthesis restores replication following Set2 loss Pai et al. find that the Set2 methyltransferase facilitates dNTP synthesis and DNA replication through promoting MBF-dependent transcription in fission yeast. Set2 loss results in reduced ribonucleotide reductase expression, reduced dNTP synthesis, altered replication origin firing, and checkpoint-dependent S-phase delay. These findings suggest how H3K36 methylation suppresses replication stress.
    Subject(s): Cell Cycle Checkpoints - genetics ; Cell Cycle Proteins - metabolism ; DNA Damage - genetics ; DNA replication ; DNA Replication - genetics ; DNA, Fungal - metabolism ; dNTP ; Down-Regulation - genetics ; Gene Expression Regulation, Fungal ; Genes, Fungal ; histone H3K36 methylation ; histone methylation ; Histone-Lysine N-Methyltransferase - metabolism ; MBF ; Mutation - genetics ; Nucleotides - metabolism ; Replication Origin - genetics ; ribonucleotide reductase ; S Phase - genetics ; Schizosaccharomyces - enzymology ; Schizosaccharomyces - genetics ; Schizosaccharomyces pombe ; Schizosaccharomyces pombe Proteins - metabolism ; Set2 ; Transcription Factors - metabolism ; Transcription, Genetic
    ISSN: 2211-1247
    E-ISSN: 2211-1247
    Source: Alma/SFX Local Collection
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
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  • 6
    Language: English
    In: Nucleic acids research, 2016-02-29, Vol.44 (4), p.1703-1717
    Description: The formation of RNA-DNA hybrids, referred to as R-loops, can promote genome instability and cancer development. Yet the mechanisms by which R-loops compromise genome instability are poorly understood. Here, we establish roles for the evolutionarily conserved Nrl1 protein in pre-mRNA splicing regulation, R-loop suppression and in maintaining genome stability. nrl1Δ mutants exhibit endogenous DNA damage, are sensitive to exogenous DNA damage, and have defects in homologous recombination (HR) repair. Concomitantly, nrl1Δ cells display significant changes in gene expression, similar to those induced by DNA damage in wild-type cells. Further, we find that nrl1Δ cells accumulate high levels of R-loops, which co-localize with HR repair factors and require Rad51 and Rad52 for their formation. Together, our findings support a model in which R-loop accumulation and subsequent DNA damage sequesters HR factors, thereby compromising HR repair at endogenously or exogenously induced DNA damage sites, leading to genome instability.
    Subject(s): Alternative Splicing - genetics ; DNA - chemistry ; DNA - genetics ; DNA Repair - genetics ; Genome Integrity, Repair and ; Genomic Instability - genetics ; Homologous Recombination - genetics ; Rad51 Recombinase - genetics ; Rad52 DNA Repair and Recombination Protein - genetics ; RNA - chemistry ; RNA - genetics ; RNA Precursors - genetics ; Schizosaccharomyces - genetics ; Schizosaccharomyces pombe Proteins - genetics ; Spliceosomes - genetics ; Spliceosomes - 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
    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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  • 8
    Language: English
    In: Cancer cell, 2015-11-09, Vol.28 (5), p.557-568
    Description: Histone H3K36 trimethylation (H3K36me3) is frequently lost in multiple cancer types, identifying it as an important therapeutic target. Here we identify a synthetic lethal interaction in which H3K36me3-deficient cancers are acutely sensitive to WEE1 inhibition. We show that RRM2, a ribonucleotide reductase subunit, is the target of this synthetic lethal interaction. RRM2 is regulated by two pathways here: first, H3K36me3 facilitates RRM2 expression through transcription initiation factor recruitment; second, WEE1 inhibition degrades RRM2 through untimely CDK activation. Therefore, WEE1 inhibition in H3K36me3-deficient cells results in RRM2 reduction, critical dNTP depletion, S-phase arrest, and apoptosis. Accordingly, this synthetic lethality is suppressed by increasing RRM2 expression or inhibiting RRM2 degradation. Finally, we demonstrate that WEE1 inhibitor AZD1775 regresses H3K36me3-deficient tumor xenografts. [Display omitted] •WEE1 inhibition selectively kills H3K36me3-deficient cancer cells•These cells are killed through dNTP starvation because of RRM2 depletion•RRM2 is regulated by H3K36me3 through transcription and WEE1 via degradation•WEE1 inhibitor AZD1775 regresses H3K36me3-deficient tumors in vivo Pfister et al. show that WEE1 inhibition selectively kills H3K36me3-deficient cancer cells through dNTP starvation resulting from RRM2 depletion. Pfister et al. further show that H3K36me3 facilitates RRM2 transcription whereas WEE1 inhibition promotes RRM2 degradation via CDK activation.
    Subject(s): Amino Acid Sequence ; Animals ; ATR inhibitor ; AZD1775 ; Base Sequence ; Blotting, Western ; Cancer ; CDK ; Cell Cycle Proteins - antagonists & inhibitors ; Cell Cycle Proteins - genetics ; Cell Cycle Proteins - metabolism ; Cell Line, Tumor ; Cell Survival - drug effects ; Cell Survival - genetics ; ChIP ; CHK1 inhibitor ; DNA replication ; Epigenetic inheritance ; epigenetic target ; Gene Expression Regulation, Neoplastic - drug effects ; H3.3K36M ; H3K36me3 ; histone modification ; Histone-Lysine N-Methyltransferase - genetics ; Histone-Lysine N-Methyltransferase - metabolism ; Histones - genetics ; Histones - metabolism ; Hospitals ; Humans ; iPOND ; KDM4A ; Lysine - genetics ; Lysine - metabolism ; Medical colleges ; Methylation - drug effects ; Mice, Inbred BALB C ; Mice, Nude ; Molecular Sequence Data ; Neoplasms - genetics ; Neoplasms - metabolism ; Neoplasms - prevention & control ; Nuclear Proteins - antagonists & inhibitors ; Nuclear Proteins - genetics ; Nuclear Proteins - metabolism ; Nucleotides - genetics ; Nucleotides - metabolism ; Protein-Tyrosine Kinases - antagonists & inhibitors ; Protein-Tyrosine Kinases - genetics ; Protein-Tyrosine Kinases - metabolism ; Pyrazoles - pharmacology ; Pyrimidines - pharmacology ; Pyrimidinones ; Reverse Transcriptase Polymerase Chain Reaction ; Ribonucleoside Diphosphate Reductase - genetics ; Ribonucleoside Diphosphate Reductase - metabolism ; RNA Interference ; RRM2 ; Sequence Homology, Amino Acid ; Sequence Homology, Nucleic Acid ; SETD2 ; Starvation ; synthetic lethality ; WEE1 inhibitor ; Xenograft Model Antitumor Assays
    ISSN: 1535-6108
    E-ISSN: 1878-3686
    Source: Cell Press Collection [ECCPC]
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  • 9
    Language: English
    In: PLoS genetics, 2021-07, Vol.17 (7), p.e1009526-e1009526
    Description: Somatic and germline mutations in the proofreading domain of the replicative DNA polymerase ε (POLE-exonuclease domain mutations, POLE-EDMs) are frequently found in colorectal and endometrial cancers and, occasionally, in other tumours. POLE-associated cancers typically display hypermutation, and a unique mutational signature, with a predominance of C 〉 A transversions in the context TCT and C 〉 T transitions in the context TCG. To understand better the contribution of hypermutagenesis to tumour development, we have modelled the most recurrent POLE-EDM (POLE-P286R) in Schizosaccharomyces pombe. Whole-genome sequencing analysis revealed that the corresponding pol2-P287R allele also has a strong mutator effect in vivo, with a high frequency of base substitutions and relatively few indel mutations. The mutations are equally distributed across different genomic regions, but in the immediate vicinity there is an asymmetry in AT frequency. The most abundant base-pair changes are TCT 〉 TAT transversions and, in contrast to human mutations, TCG 〉 TTG transitions are not elevated, likely due to the absence of cytosine methylation in fission yeast. The pol2-P287R variant has an increased sensitivity to elevated dNTP levels and DNA damaging agents, and shows reduced viability on depletion of the Pfh1 helicase. In addition, S phase is aberrant and RPA foci are elevated, suggestive of ssDNA or DNA damage, and the pol2-P287R mutation is synthetically lethal with rad3 inactivation, indicative of checkpoint activation. Significantly, deletion of genes encoding some translesion synthesis polymerases, most notably Pol κ, partially suppresses pol2-P287R hypermutation, indicating that polymerase switching contributes to this phenotype.
    Subject(s): Biology and Life Sciences ; Cell cycle ; Checkpoint Kinase 2 - genetics ; Cytosine ; Deoxyribonucleic acid ; DNA ; DNA biosynthesis ; DNA damage ; DNA helicase ; DNA Helicases - genetics ; DNA polymerase ; DNA Polymerase II - genetics ; DNA Polymerase II - metabolism ; DNA Replication ; DNA-directed DNA polymerase ; Editing ; Endometrial cancer ; Endometrium ; Enzymes ; Exonuclease ; Experiments ; Genome, Fungal ; Genomes ; Genotype & phenotype ; Humans ; Medicine and Health Sciences ; Mutation ; Neoplasms - genetics ; Phenotypes ; Poly-ADP-Ribose Binding Proteins - genetics ; Proofreading ; Research and Analysis Methods ; S phase ; S Phase - genetics ; Schizosaccharomyces - genetics ; Schizosaccharomyces - metabolism ; Schizosaccharomyces pombe Proteins - genetics ; Schizosaccharomyces pombe Proteins - metabolism ; Transcription activation ; Tumors ; Whole genome sequencing ; Yeast
    ISSN: 1553-7404
    ISSN: 1553-7390
    E-ISSN: 1553-7404
    Source: Academic Search Ultimate
    Source: PubMed Central
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
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  • 10
    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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