placeholder
and
and

Your email was sent successfully. Check your inbox.

An error occurred while sending the email. Please try again.

Proceed reservation?

Export
Filter
Document type
Language
Year
  • 1
    Language: English
    In: Cell reports (Cambridge), 2014-06-26, Vol.7 (6), p.2006-2018
    Description: Modulating chromatin through histone methylation orchestrates numerous cellular processes. SETD2-dependent trimethylation of histone H3K36 is associated with active transcription. Here, we define a role for H3K36 trimethylation in homologous recombination (HR) repair in human cells. We find that depleting SETD2 generates a mutation signature resembling RAD51 depletion at I-SceI-induced DNA double-strand break (DSB) sites, with significantly increased deletions arising through microhomology-mediated end-joining. We establish a presynaptic role for SETD2 methyltransferase in HR, where it facilitates the recruitment of C-terminal binding protein interacting protein (CtIP) and promotes DSB resection, allowing Replication Protein A (RPA) and RAD51 binding to DNA damage sites. Furthermore, reducing H3K36me3 levels by overexpressing KDM4A/JMJD2A, an oncogene and H3K36me3/2 demethylase, or an H3.3K36M transgene also reduces HR repair events. We propose that error-free HR repair within H3K36me3-decorated transcriptionally active genomic regions promotes cell homeostasis. Moreover, these findings provide insights as to why oncogenic mutations cluster within the H3K36me3 axis. [Display omitted] •A role for SETD2 in DSB resection and homologous recombination repair•Histone H3K36me3 is required for homologous recombination•SETD2 and RAD51 suppress mutations arising from microhomology-mediated end-joining•Mutations affecting H3K36me3 levels may promote tumorigenesis The SETD2 gene encodes the histone H3K36 trimethyltransferase. Pfister et al. now show that human SETD2-dependent H3K36me3 maintains genome stability by promoting error-free DNA repair through homologous recombination (HR). Upon DNA damage, SETD2-depleted cells exhibit reduced DNA resection, impaired recruitment of early HR factors, and increased utilization of the error-prone microhomology-mediated end-joining repair pathway. Eliminating H3K36me3 by overexpressing the oncogene KDM4A also impairs HR. Thus, H3K36me3 suppresses tumorigenesis by promoting accurate DNA repair.
    Subject(s): DNA Repair ; Genomic Instability ; Histone-Lysine N-Methyltransferase - genetics ; Histone-Lysine N-Methyltransferase - metabolism ; Histones - genetics ; Histones - metabolism ; Homologous Recombination ; Humans ; Medicin och hälsovetenskap ; Methylation ; Protein Binding ; Rad51 Recombinase - genetics ; Rad51 Recombinase - metabolism ; Recombinational DNA Repair ; Transfection
    ISSN: 2211-1247
    E-ISSN: 2211-1247
    Source: Alma/SFX Local Collection
    Source: SWEPUB Freely available online
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 2
    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]
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 3
    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
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 4
    Language: English
    In: Nucleic acids research, 2016-07-08, Vol.44 (12), p.5743-5757
    Description: DNA double-strand breaks (DSBs) are toxic lesions, which if improperly repaired can result in cell death or genomic instability. DSB repair is usually facilitated by the classical non-homologous end joining (C-NHEJ), or homologous recombination (HR) pathways. However, a mutagenic alternative NHEJ pathway, microhomology-mediated end joining (MMEJ), can also be deployed. While MMEJ is suppressed by C-NHEJ, the relationship between HR and MMEJ is less clear. Here, we describe a role for HR genes in suppressing MMEJ in human cells. By monitoring DSB mis-repair using a sensitive HPRT assay, we found that depletion of HR proteins, including BRCA2, BRCA1 or RPA, resulted in a distinct mutational signature associated with significant increases in break-induced mutation frequencies, deletion lengths and the annealing of short regions of microhomology (2-6 bp) across the break-site. This signature was dependent on CtIP, MRE11, POLQ and PARP, and thus indicative of MMEJ. In contrast to CtIP or MRE11, depletion of BRCA1 resulted in increased partial resection and MMEJ, thus revealing a functional distinction between these early acting HR factors. Together these findings indicate that HR factors suppress mutagenic MMEJ following DSB resection.
    Subject(s): Base Sequence ; Biological Assay ; BRCA1 Protein - antagonists & inhibitors ; BRCA1 Protein - genetics ; BRCA1 Protein - metabolism ; BRCA2 Protein - antagonists & inhibitors ; BRCA2 Protein - genetics ; BRCA2 Protein - metabolism ; Carrier Proteins - genetics ; Carrier Proteins - metabolism ; Cell Line, Tumor ; DNA - metabolism ; DNA Breaks, Double-Stranded ; DNA End-Joining Repair ; DNA-Binding Proteins - genetics ; DNA-Binding Proteins - metabolism ; DNA-Directed DNA Polymerase - genetics ; DNA-Directed DNA Polymerase - metabolism ; Endodeoxyribonucleases ; Epithelial Cells - cytology ; Epithelial Cells - metabolism ; Fibroblasts - cytology ; Fibroblasts - metabolism ; Genome Integrity, Repair and ; Humans ; MRE11 Homologue Protein ; Mutation ; Nuclear Proteins - genetics ; Nuclear Proteins - metabolism ; Osteoblasts - cytology ; Osteoblasts - metabolism ; Poly(ADP-ribose) Polymerases - genetics ; Poly(ADP-ribose) Polymerases - metabolism ; Recombinational DNA Repair ; Replication Protein A - antagonists & inhibitors ; Replication Protein A - genetics ; Replication Protein A - metabolism ; RNA, Small Interfering - genetics ; RNA, Small Interfering - metabolism ; Sequence Alignment ; Sequence Homology, Nucleic Acid
    ISSN: 0305-1048
    E-ISSN: 1362-4962
    Source: PubMed Central
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 5
    Article
    Article
    2015
    ISSN: 1538-4101 
    Language: English
    In: Cell cycle (Georgetown, Tex.), 2015-05-03, Vol.14 (9), p.1353-1353
    Subject(s): Cell Cycle & Views ; Chromosome Segregation - drug effects ; Fluorouracil - pharmacology ; Schizosaccharomyces - metabolism
    ISSN: 1538-4101
    E-ISSN: 1551-4005
    Source: PubMed Central
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 6
    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
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 7
    Language: English
    In: Nucleic acids research, 2018-09-06, Vol.46 (15), p.7731-7746
    Description: Abstract The nuclear pore complex (NPC) machinery is emerging as an important determinant in the maintenance of genome integrity and sensitivity to DNA double-strand break (DSB)-inducing agents, such as ionising radiation (IR). In this study, using a high-throughput siRNA screen, we identified the central channel NPC protein Nup54, and concomitantly its molecular partners Nup62 and Nup58, as novel factors implicated in radiosensitivity. Nup54 depletion caused an increase in cell death by mitotic catastrophe after IR, and specifically enhanced both the duration of the G2 arrest and the radiosensitivity of cells that contained replicated DNA at the time of IR exposure. Nup54-depleted cells also exhibited increased formation of chromosome aberrations arisen from replicated DNA. Interestingly, we found that Nup54 is epistatic with the homologous recombination (HR) factor Rad51. Moreover, using specific DNA damage repair reporters, we observed a decreased HR repair activity upon Nup54 knockdown. In agreement with a role in HR repair, we also demonstrated a decreased formation of HR-linked DNA synthesis foci and sister chromatid exchanges after IR in cells depleted of Nup54. Our study reveals a novel role for Nup54 in the response to IR and the maintenance of HR-mediated genome integrity.
    Subject(s): Cell Line, Tumor ; Cell Survival - genetics ; Cell Survival - radiation effects ; DNA - genetics ; DNA - metabolism ; DNA Breaks, Double-Stranded - radiation effects ; DNA Replication ; Genome Integrity, Repair and ; HeLa Cells ; Humans ; MCF-7 Cells ; Nuclear Pore - genetics ; Nuclear Pore - metabolism ; Nuclear Pore Complex Proteins - genetics ; Nuclear Pore Complex Proteins - metabolism ; Rad51 Recombinase - genetics ; Rad51 Recombinase - metabolism ; Radiation, Ionizing ; Recombinational DNA Repair ; RNA Interference ; Sister Chromatid Exchange - radiation effects
    ISSN: 0305-1048
    E-ISSN: 1362-4962
    Source: PubMed Central
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 8
    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
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 9
    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
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 10
    Language: English
    In: Nature structural & molecular biology, 2014-08, Vol.21 (8), p.655-657
    Description: Mechanisms of DNA damage repair within actively transcribed genes are poorly understood. Five new reports shed light on the contributions of chromatin to this process by uncovering roles for histone H3 Lys36 methylation, a post-translational modification previously linked to transcription elongation, in the control of DNA-damage signaling and double strand break repair.
    Subject(s): Cells ; Chromatin ; DNA Breaks, Double-Stranded ; DNA damage ; DNA Repair ; Fungal Proteins - physiology ; Genetic aspects ; Histone-Lysine N-Methyltransferase - physiology ; Histones - metabolism ; Humans ; Protein Processing, Post-Translational ; Research ; Saccharomycetales - genetics ; Schizosaccharomyces - genetics
    ISSN: 1545-9993
    E-ISSN: 1545-9985
    Source: Academic Search Ultimate
    Source: Get It Now
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
Close ⊗
This website uses cookies and the analysis tool Matomo. More information can be found here...