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  • 1
    Language: English
    In: eLife, 2016-07-12, Vol.5
    Description: Eukaryotic mismatch repair (MMR) utilizes single-strand breaks as signals to target the strand to be repaired. DNA-bound PCNA is also presumed to direct MMR. The MMR capability must be limited to a post-replicative temporal window during which the signals are available. However, both identity of the signal(s) involved in the retention of this temporal window and the mechanism that maintains the MMR capability after DNA synthesis remain unclear. Using Xenopus egg extracts, we discovered a mechanism that ensures long-term retention of the MMR capability. We show that DNA-bound PCNA induces strand-specific MMR in the absence of strand discontinuities. Strikingly, MutSα inhibited PCNA unloading through its PCNA-interacting motif, thereby extending significantly the temporal window permissive to strand-specific MMR. Our data identify DNA-bound PCNA as the signal that enables strand discrimination after the disappearance of strand discontinuities, and uncover a novel role of MutSα in the retention of the post-replicative MMR capability.
    Subject(s): Animals ; Biochemistry ; Cell Extracts ; Cells, Cultured ; Deoxyribonucleic acid ; DNA ; DNA - metabolism ; DNA biosynthesis ; DNA methylation ; DNA Mismatch Repair ; DNA replication ; Genes and Chromosomes ; Mismatch repair ; Mutation ; MutS DNA Mismatch-Binding Protein - metabolism ; MutSα ; Proliferating cell nuclear antigen ; Proliferating Cell Nuclear Antigen - metabolism ; Protein Binding ; Sensors ; Unloading ; Xenopus ; Xenopus egg extract ; Zygote - enzymology
    ISSN: 2050-084X
    E-ISSN: 2050-084X
    Source: PubMed Central
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
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  • 2
    Language: English
    In: The EMBO journal, 2012-05-02, Vol.31 (9), p.2182-2194
    Description: The CMG complex composed of Mcm2‐7, Cdc45 and GINS is postulated to be the eukaryotic replicative DNA helicase, whose activation requires sequential recruitment of replication proteins onto Mcm2‐7. Current models suggest that Mcm10 is involved in assembly of the CMG complex, and in tethering of DNA polymerase α at replication forks. Here, we report that Mcm10 is required for origin DNA unwinding after association of the CMG components with replication origins in fission yeast. A combination of promoter shut‐off and the auxin‐inducible protein degradation (off‐aid) system efficiently depleted cellular Mcm10 to 〈0.5% of the wild‐type level. Depletion of Mcm10 did not affect origin loading of Mcm2‐7, Cdc45 or GINS, but impaired recruitment of RPA and DNA polymerases. Mutations in a conserved zinc finger of Mcm10 abolished RPA loading after recruitment of Mcm10. These results show that Mcm10, together with the CMG components, plays a novel essential role in origin DNA unwinding through its zinc‐finger function. Acute removal of the fission yeast Mcm10 replication protein via an auxin‐inducible degron shows that it activates DNA unwinding and initiation independent of assembling the Cdc45–Mcm2‐7–GINS helicase complex.
    Subject(s): Cell Cycle Proteins - metabolism ; Chromosomal Proteins, Non-Histone - metabolism ; DNA polymerase ; DNA replication ; DNA, Fungal - metabolism ; Eukaryotes ; Fungal Proteins - metabolism ; Leukocyte Common Antigens - metabolism ; Mcm2-7 ; Molecular biology ; off-aid ; Proteins ; RPA ; Schizosaccharomyces pombe ; Yeasts ; zinc finger
    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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  • 3
    Language: English
    In: Current genetics, 2019-04-17, Vol.65 (5), p.1089-1098
    Description: The centromere region of chromosomes consists of repetitive DNA sequences, and is, therefore, one of the fragile sites of chromosomes in many eukaryotes. In the core region, the histone H3 variant CENP-A forms centromere-specific nucleosomes that are required for kinetochore formation. In the pericentromeric region, histone H3 is methylated at lysine 9 (H3K9) and heterochromatin is formed. The transcription of pericentromeric repeats by RNA polymerase II is strictly repressed by heterochromatin. However, the role of the transcriptional silencing of the pericentromeric repeats remains largely unclear. Here, we focus on the chromosomal rearrangements that occur at the repetitive centromeres, and highlight our recent studies showing that transcriptional silencing by heterochromatin suppresses gross chromosomal rearrangements (GCRs) at centromeres in fission yeast. Inactivation of the Clr4 methyltransferase, which is essential for the H3K9 methylation, increased GCRs with breakpoints located in centromeric repeats. However, mutations in RNA polymerase II or the transcription factor Tfs1/TFIIS, which promotes restart of RNA polymerase II following its backtracking, reduced the GCRs that occur in the absence of Clr4, demonstrating that heterochromatin suppresses GCRs by repressing the Tfs1-dependent transcription. We also discuss how the transcriptional restart gives rise to chromosomal rearrangements at centromeres.
    Subject(s): Biochemistry ; Biomedical and Life Sciences ; Breakpoints ; Cell Biology ; Centromere - genetics ; Centromeres ; Chromatin ; Chromosomal Instability ; Chromosome rearrangements ; Chromosomes ; Deactivation ; Deoxyribonucleic acid ; DNA ; DNA-directed RNA polymerase ; Eukaryotes ; Fragile sites ; Gene sequencing ; Gene Silencing ; general ; Genetics & Heredity ; Heterochromatin ; Heterochromatin - genetics ; Histone H3 ; Inactivation ; Life Sciences ; Life Sciences & Biomedicine ; Lysine ; Methods ; Methylation ; Methyltransferase ; Microbial Genetics and Genomics ; Microbiology ; Mutation ; Nucleosomes ; Nucleotide sequence ; Plant Sciences ; Proteomics ; Repetitive Sequences, Nucleic Acid ; Review ; Ribonucleic acid ; RNA ; RNA polymerase ; RNA polymerase II ; Schizosaccharomyces - genetics ; Science & Technology ; Structure ; Transcription, Genetic ; Transcriptional Activation ; Translocation, Genetic ; Usage ; Yeast
    ISSN: 0172-8083
    E-ISSN: 1432-0983
    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: The EMBO journal, 2018-08-01, Vol.37 (15), p.n/a
    Description: DNA replication initiates at many discrete loci on eukaryotic chromosomes, and individual replication origins are regulated under a spatiotemporal program. However, the underlying mechanisms of this regulation remain largely unknown. In the fission yeast Schizosaccharomyces pombe, the telomere‐binding protein Taz1, ortholog of human TRF1/TRF2, regulates a subset of late replication origins by binding to the telomere‐like sequence near the origins. Here, we showed using a lacO/LacI‐GFP system that Taz1‐dependent late origins were predominantly localized at the nuclear periphery throughout interphase, and were localized adjacent to the telomeres in the G1/S phase. The peripheral localization that depended on the nuclear membrane protein Bqt4 was not necessary for telomeric association and replication‐timing control of the replication origins. Interestingly, the shelterin components Rap1 and Poz1 were required for replication‐timing control and telomeric association of Taz1‐dependent late origins, and this requirement was bypassed by a minishelterin Tpz1‐Taz1 fusion protein. Our results suggest that Taz1 suppresses replication initiation through shelterin‐mediated telomeric association of the origins at the onset of S phase. Synopsis Replication‐timing control of late‐firing origins in fission yeast chromosome arms involves Taz1 shelterin‐mediated tethering of the origins to the proximity of telomeres, where replication initiation is inhibited independent of subnuclear localization. Internal Taz1‐dependent late replication origins are localized close to telomeres in G1/S. Shelterin components are necessary for replication‐timing control and origin localization. Nuclear periphery localization is not necessary for late‐timing control. A Tpz1‐Taz1 fusion “mini‐shelterin” restores late‐timing control and telomeric association of origins. Timing control of late‐firing chromosome arm origins in fission yeast involves Taz1‐mediated origin tethering to the proximity of telomeres, where replication initiation is inhibited independent of subnuclear localization.
    Subject(s): chromatin organization ; Chromatin, Epigenetics, Genomics & Functional Genomics ; Chromosomes ; Deoxyribonucleic acid ; DNA ; DNA biosynthesis ; DNA Replication - genetics ; DNA Replication, Repair & Recombination ; DNA-Binding Proteins - metabolism ; Eukaryotes ; Fusion protein ; G1 Phase - genetics ; Localization ; Membrane proteins ; Membrane Proteins - metabolism ; Nuclear Proteins - metabolism ; Origins ; Proteins ; Rap1 ; Rap1 protein ; Recombinant Fusion Proteins - metabolism ; Replication ; Replication initiation ; Replication Origin - genetics ; Replication origins ; replication timing ; S phase ; S Phase - genetics ; Schizosaccharomyces - genetics ; Schizosaccharomyces pombe Proteins - genetics ; Schizosaccharomyces pombe Proteins - metabolism ; Taz1 ; Telomerase ; telomere ; Telomere - metabolism ; Telomere-binding protein ; Telomere-Binding Proteins - genetics ; Telomere-Binding Proteins - metabolism ; Telomeres ; Telomeric Repeat Binding Protein 2 - metabolism ; Tethering ; TRF2 protein ; Yeast
    ISSN: 0261-4189
    E-ISSN: 1460-2075
    Source: HighWire Press (Free Journals)
    Source: PubMed Central
    Source: Alma/SFX Local Collection
    Source: Get It Now
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  • 5
    Language: English
    In: The EMBO journal, 2007-03-07, Vol.26 (5), p.1327-1339
    Description: DNA replication of eukaryotic chromosomes initiates at a number of discrete loci, called replication origins. Distribution and regulation of origins are important for complete duplication of the genome. Here, we determined locations of Orc1 and Mcm6, components of pre‐replicative complex (pre‐RC), on the whole genome of Schizosaccharomyces pombe using a high‐resolution tiling array. Pre‐RC sites were identified in 460 intergenic regions, where Orc1 and Mcm6 colocalized. By mapping of 5‐bromo‐2′‐deoxyuridine (BrdU)‐incorporated DNA in the presence of hydroxyurea (HU), 307 pre‐RC sites were identified as early‐firing origins. In contrast, 153 pre‐RC sites without BrdU incorporation were considered to be late and/or inefficient origins. Inactivation of replication checkpoint by Cds1 deletion resulted in BrdU incorporation with HU specifically at the late origins. Early and late origins tend to distribute separately in large chromosome regions. Interestingly, pericentromeric heterochromatin and the silent mating‐type locus replicated in the presence of HU, whereas the inner centromere or subtelomeric heterochromatin did not. Notably, MCM did not bind to inner centromeres where origin recognition complex was located. Thus, replication is differentially regulated in chromosome domains.
    Subject(s): Cell cycle ; Cell Cycle - genetics ; Cell Cycle Proteins - genetics ; Cell Cycle Proteins - metabolism ; centromere ; Centromere - metabolism ; Checkpoint Kinase 2 ; Chromosomes ; Chromosomes, Fungal ; Deoxyribonucleic acid ; Dideoxynucleosides - metabolism ; DNA ; DNA microarray ; DNA Replication - drug effects ; DNA Replication - genetics ; DNA, Intergenic - genetics ; Electrophoresis, Gel, Two-Dimensional ; fission yeast ; Genome, Fungal ; Genomics ; Heterochromatin - metabolism ; Hydroxyurea - pharmacology ; Minichromosome Maintenance Complex Component 6 ; Molecular biology ; Oligonucleotide Array Sequence Analysis ; Origin Recognition Complex - genetics ; Origin Recognition Complex - metabolism ; Protein-Serine-Threonine Kinases - genetics ; Protein-Serine-Threonine Kinases - metabolism ; replication origin ; Replication Origin - genetics ; Schizosaccharomyces - drug effects ; Schizosaccharomyces - genetics ; Schizosaccharomyces - metabolism ; Schizosaccharomyces pombe ; Schizosaccharomyces pombe Proteins - genetics ; Schizosaccharomyces pombe Proteins - metabolism ; subtelomere ; 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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  • 6
    Language: English
    In: Genes & development, 2018-06-01, Vol.32 (11-12), p.806-821
    Description: Post-replicative correction of replication errors by the mismatch repair (MMR) system is critical for suppression of mutations. Although the MMR system may need to handle nucleosomes at the site of chromatin replication, how MMR occurs in the chromatin environment remains unclear. Here, we show that nucleosomes are excluded from a 〉1-kb region surrounding a mismatched base pair in egg extracts. The exclusion was dependent on the Msh2-Msh6 mismatch recognition complex but not the Mlh1-containing MutL homologs and counteracts both the HIRA- and CAF-1 (chromatin assembly factor 1)-mediated chromatin assembly pathways. We further found that the Smarcad1 chromatin remodeling ATPase is recruited to mismatch-carrying DNA in an Msh2-dependent but Mlh1-independent manner to assist nucleosome exclusion and that Smarcad1 facilitates the repair of mismatches when nucleosomes are preassembled on DNA. In budding yeast, deletion of , the homolog of Smarcad1, showed a synergistic increase of spontaneous mutations in combination with or deletion but no significant increase with deletion. Genetic analyses also suggested that the function of Fun30 in MMR is to counteract CAF-1. Our study uncovers that the eukaryotic MMR system has an ability to exclude local nucleosomes and identifies Smarcad1/Fun30 as an accessory factor for the MMR reaction.
    Subject(s): chromatin ; mismatch repair ; nucleosome ; Research Paper ; Xenopus egg extract ; yeast
    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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  • 7
    Language: English
    In: Nature cell biology, 2009-03, Vol.11 (3), p.357-362
    Description: Heterochromatin is a structurally compacted region of chromosomes in which transcription and recombination are inactivated. DNA replication is temporally regulated in heterochromatin, but the molecular mechanism for regulation has not been elucidated. Among heterochromatin loci in Schizosaccharomyces pombe, the pericentromeric region and the silent mating-type (mat) locus replicate in early S phase, whereas the sub-telomeric region does not, suggesting complex mechanisms for regulation of replication in heterochromatic regions. Here, we show that Swi6, an S. pombe counterpart of heterochromatin protein 1 (HP1), is required for early replication of the pericentromeric region and the mat locus. Origin-loading of Sld3, which depends on Dfp1/Dbf4-dependent kinase Cdc7 (DDK), is stimulated by Swi6. An HP1-binding motif within Dfp1 is required for interaction with Swi6 in vitro and for early replication of the pericentromeric region and mat locus. Tethering of Dfp1 to the pericentromeric region and mat locus in swi6-deficient cells restores early replication of these loci. Our results show that a heterochromatic protein positively regulates initiation of replication in silenced chromatin by interacting with an essential kinase.
    Subject(s): Amino Acid Motifs ; Cellular proteins ; Centromere - metabolism ; Chromatin ; Chromosomal Proteins, Non-Histone - metabolism ; DNA replication ; DNA Replication Timing ; Genes, Mating Type, Fungal ; Heterochromatin - metabolism ; Models, Biological ; Physiological aspects ; Point Mutation - genetics ; Protein Binding ; Protein Transport ; Replication Origin ; S Phase ; Schizosaccharomyces - genetics ; Schizosaccharomyces pombe ; Schizosaccharomyces pombe Proteins - chemistry ; Schizosaccharomyces pombe Proteins - metabolism
    ISSN: 1465-7392
    E-ISSN: 1476-4679
    Source: Academic Search Ultimate
    Source: Nature Journals Online
    Source: Get It Now
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  • 8
    Language: English
    In: Nucleic acids research, 2017-11-02, Vol.45 (19), p.11222-11235
    Description: Centromeres that are essential for faithful segregation of chromosomes consist of unique DNA repeats in many eukaryotes. Although recombination is under-represented around centromeres during meiosis, little is known about recombination between centromere repeats in mitotic cells. Here, we compared spontaneous recombination that occurs between ade6B/ade6X inverted repeats integrated at centromere 1 (cen1) or at a non-centromeric ura4 locus in fission yeast. Remarkably, distinct mechanisms of homologous recombination (HR) were observed in centromere and non-centromere regions. Rad51-dependent HR that requires Rad51, Rad54 and Rad52 was predominant in the centromere, whereas Rad51-independent HR that requires Rad52 also occurred in the arm region. Crossovers between inverted repeats (i.e. inversions) were under-represented in the centromere as compared to the arm region. While heterochromatin was dispensable, Mhf1/CENP-S, Mhf2/CENP-X histone-fold proteins and Fml1/FANCM helicase were required to suppress crossovers. Furthermore, Mhf1 and Fml1 were found to prevent gross chromosomal rearrangements mediated by centromere repeats. These data for the first time uncovered the regulation of mitotic recombination between DNA repeats in centromeres and its physiological role in maintaining genome integrity.
    Subject(s): Centromere - genetics ; Chromosomal Proteins, Non-Histone - genetics ; Chromosomal Proteins, Non-Histone - metabolism ; DNA Helicases - genetics ; DNA Helicases - metabolism ; DNA, Fungal - genetics ; DNA, Fungal - metabolism ; Genome Integrity, Repair and ; Genome, Fungal - genetics ; Homologous Recombination ; Mitosis - genetics ; Models, Genetic ; Rad51 Recombinase - genetics ; Rad51 Recombinase - metabolism ; Rad52 DNA Repair and Recombination Protein - genetics ; Rad52 DNA Repair and Recombination Protein - metabolism ; Schizosaccharomyces - genetics ; Schizosaccharomyces - metabolism ; Schizosaccharomyces pombe Proteins - genetics ; 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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  • 9
    Language: English
    In: Genes & development, 2012-09-15, Vol.26 (18), p.2050-2062
    Description: In eukaryotes, the replication of chromosome DNA is coordinated by a replication timing program that temporally regulates the firing of individual replication origins. However, the molecular mechanism underlying the program remains elusive. Here, we report that the telomere-binding protein Taz1 plays a crucial role in the control of replication timing in fission yeast. A DNA element located proximal to a late origin in the chromosome arm represses initiation from the origin in early S phase. Systematic deletion and substitution experiments demonstrated that two tandem telomeric repeats are essential for this repression. The telomeric repeats recruit Taz1, a counterpart of human TRF1 and TRF2, to the locus. Genome-wide analysis revealed that Taz1 regulates about half of chromosomal late origins, including those in subtelomeres. The Taz1-mediated mechanism prevents Dbf4-dependent kinase (DDK)-dependent Sld3 loading onto the origins. Our results demonstrate that the replication timing program in fission yeast uses the internal telomeric repeats and binding of Taz1.
    Subject(s): Base Sequence ; chromosome ; Chromosomes ; DNA Replication - physiology ; DNA, Fungal - genetics ; DNA, Fungal - metabolism ; DNA-Binding Proteins - metabolism ; Eukaryotes ; initiation of replication ; Molecular Sequence Data ; Protein Binding ; Protein Transport ; Replication Origin - physiology ; replication timing ; Research Paper ; Schizosaccharomyces - genetics ; Schizosaccharomyces - metabolism ; Schizosaccharomyces - physiology ; Schizosaccharomyces pombe Proteins - genetics ; Schizosaccharomyces pombe Proteins - metabolism ; Taz1 ; telomere ; Telomere-Binding Proteins - genetics ; Telomere-Binding Proteins - metabolism ; Telomeres
    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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  • 10
    Language: English
    In: Nucleic acids research, 2016-12-15, Vol.44 (22), p.10744-10757
    Description: Centromeres consist of DNA repeats in many eukaryotes. Non-allelic homologous recombination (HR) between them can result in gross chromosomal rearrangements (GCRs). In fission yeast, Rad51 suppresses isochromosome formation that occurs between inverted repeats in the centromere. However, how the HR enzyme prevents homology-mediated GCRs remains unclear. Here, we provide evidence that Rad51 with the aid of the Swi/Snf-type motor protein Rad54 promotes non-crossover recombination between centromere repeats to prevent isochromosome formation. Mutations in Rad51 and Rad54 epistatically increased the rates of isochromosome formation and chromosome loss. In sharp contrast, these mutations decreased gene conversion between inverted repeats in the centromere. Remarkably, analysis of recombinant DNAs revealed that rad51 and rad54 increase the proportion of crossovers. In the absence of Rad51, deletion of the structure-specific endonuclease Mus81 decreased both crossovers and isochromosomes, while the cdc27/pol32-D1 mutation, which impairs break-induced replication, did not. We propose that Rad51 and Rad54 promote non-crossover recombination between centromere repeats on the same chromatid, thereby suppressing crossover between non-allelic repeats on sister chromatids that leads to chromosomal rearrangements. Furthermore, we found that Rad51 and Rad54 are required for gene silencing in centromeres, suggesting that HR also plays a role in the structure and function of centromeres.
    Subject(s): Centromere ; Chromatids ; Chromosomes, Fungal ; Crossing Over, Genetic ; DNA Helicases - physiology ; DNA, Fungal - genetics ; Genome Integrity, Repair and ; Rad51 Recombinase - physiology ; Recombinational DNA Repair ; Repetitive Sequences, Nucleic Acid ; Schizosaccharomyces - genetics ; Schizosaccharomyces - metabolism ; Schizosaccharomyces pombe Proteins - physiology
    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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