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  1. Article ; Online: RECQL4 is not critical for firing of human DNA replication origins.

    Padayachy, Laura / Ntallis, Sotirios G / Halazonetis, Thanos D

    Scientific reports

    2024  Volume 14, Issue 1, Page(s) 7708

    Abstract: Human RECQL4, a member of the RecQ helicase family, plays a role in maintaining genomic stability, but its precise function remains unclear. The N-terminus of RECQL4 has similarity to Sld2, a protein required for the firing of DNA replication origins in ... ...

    Abstract Human RECQL4, a member of the RecQ helicase family, plays a role in maintaining genomic stability, but its precise function remains unclear. The N-terminus of RECQL4 has similarity to Sld2, a protein required for the firing of DNA replication origins in budding yeast. Consistent with this sequence similarity, the Xenopus laevis homolog of RECQL4 has been implicated in initiating DNA replication in egg extracts. To determine whether human RECQL4 is required for firing of DNA replication origins, we generated cells in which both RECQL4 alleles were targeted, resulting in either lack of protein expression (knock-out; KO) or expression of a full-length, mutant protein lacking helicase activity (helicase-dead; HD). Interestingly, both the RECQL4 KO and HD cells were viable and exhibited essentially identical origin firing profiles as the parental cells. Analysis of the rate of fork progression revealed increased rates in the RECQL4 KO cells, which might be indicative of decreased origin firing efficiency. Our results are consistent with human RECQL4 having a less critical role in firing of DNA replication origins, than its budding yeast homolog Sld2.
    MeSH term(s) Animals ; Humans ; Replication Origin ; RecQ Helicases/genetics ; RecQ Helicases/metabolism ; DNA Replication ; Xenopus laevis/metabolism ; DNA/metabolism
    Chemical Substances RecQ Helicases (EC 3.6.4.12) ; DNA (9007-49-2) ; RECQL4 protein, human (EC 3.6.1.-)
    Language English
    Publishing date 2024-04-02
    Publishing country England
    Document type Journal Article
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-024-58404-0
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Beating cancer one carbon at a time.

    Dionellis, Vasilis S / Halazonetis, Thanos D

    Nature cancer

    2022  Volume 3, Issue 2, Page(s) 141–142

    MeSH term(s) Carbon ; Humans ; Neoplasms/diagnosis ; Time Factors
    Chemical Substances Carbon (7440-44-0)
    Language English
    Publishing date 2022-02-28
    Publishing country England
    Document type Journal Article ; Comment
    ISSN 2662-1347
    ISSN (online) 2662-1347
    DOI 10.1038/s43018-022-00333-w
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Delayed DNA break repair for genome stability.

    Petropoulos, Michalis / Halazonetis, Thanos D

    Nature cell biology

    2021  Volume 23, Issue 10, Page(s) 1055–1057

    MeSH term(s) DNA Breaks ; DNA Repair/genetics ; Genomic Instability ; Humans
    Language English
    Publishing date 2021-07-10
    Publishing country England
    Document type Journal Article ; Comment
    ZDB-ID 1474722-4
    ISSN 1476-4679 ; 1465-7392
    ISSN (online) 1476-4679
    ISSN 1465-7392
    DOI 10.1038/s41556-021-00769-9
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 5169: Show issues Location:
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    Jg. 1995 - 2021: Lesesall (2.OG)
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  4. Article ; Online: High-resolution mapping of mitotic DNA synthesis under conditions of replication stress in cultured cells.

    Groelly, Florian J / Dagg, Rebecca A / Mailler, Jonathan / Halazonetis, Thanos D / Tarsounas, Madalena

    STAR protocols

    2023  Volume 4, Issue 1, Page(s) 101970

    Abstract: Cells experiencing DNA replication stress enter mitosis with under-replicated DNA, which activates a repair mechanism known as mitotic DNA synthesis (MiDAS). Here we describe a protocol to identify at genome wide and at high resolution the genomic sites ... ...

    Abstract Cells experiencing DNA replication stress enter mitosis with under-replicated DNA, which activates a repair mechanism known as mitotic DNA synthesis (MiDAS). Here we describe a protocol to identify at genome wide and at high resolution the genomic sites where MiDAS occurs in cells exposed to aphidicolin. We use EdU incorporation to label nascent DNA in mitotic cells, followed by isolation of the EdU-labeled DNA and next-generation sequencing. For complete details on the use and execution of this protocol, please refer to Groelly et al. (2022)
    MeSH term(s) DNA Replication/genetics ; DNA/genetics ; DNA/metabolism ; Cells, Cultured ; Mitosis/genetics ; DNA Repair
    Chemical Substances DNA (9007-49-2)
    Language English
    Publishing date 2023-01-03
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 2666-1667
    ISSN (online) 2666-1667
    DOI 10.1016/j.xpro.2022.101970
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: A method to sequence genomic sites of mitotic DNA synthesis in mammalian cells.

    Mailler, Jonathan / Padayachy, Laura / Halazonetis, Thanos D

    Methods in enzymology

    2021  Volume 661, Page(s) 283–304

    Abstract: Under normal conditions, the genome of eukaryotic cells is faithfully replicated during S phase. However, in cells exposed to DNA polymerase inhibitors, some regions of the genome may fail to be replicated prior to mitotic entry. To prevent chromosomal ... ...

    Abstract Under normal conditions, the genome of eukaryotic cells is faithfully replicated during S phase. However, in cells exposed to DNA polymerase inhibitors, some regions of the genome may fail to be replicated prior to mitotic entry. To prevent chromosomal breakage and loss of genomic information, mitotic DNA synthesis (MiDAS) completes replication of the genome prior to the onset of anaphase. We have developed a protocol that allows one to map the genomic regions that are replicated by MiDAS in mammalian cells. The protocol involves incorporation of a thymidine analog in nascent DNA in mitotic cells and then capture and high throughput sequencing of the nascent DNA. With this approach, sites of MiDAS can be identified at high resolution.
    MeSH term(s) Animals ; DNA/genetics ; DNA/metabolism ; DNA Repair ; DNA Replication ; Genomics ; Mammals/genetics ; Mammals/metabolism ; Mitosis/genetics
    Chemical Substances DNA (9007-49-2)
    Language English
    Publishing date 2021-09-11
    Publishing country United States
    Document type Journal Article
    ISSN 1557-7988
    ISSN (online) 1557-7988
    DOI 10.1016/bs.mie.2021.08.013
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Homozygous substitution of threonine 191 by proline in polymerase η causes Xeroderma pigmentosum variant.

    Ricciardiello, Roberto / Forleo, Giulia / Cipolla, Lina / van Winckel, Geraldine / Marconi, Caterina / Nouspikel, Thierry / Halazonetis, Thanos D / Zgheib, Omar / Sabbioneda, Simone

    Scientific reports

    2024  Volume 14, Issue 1, Page(s) 1117

    Abstract: DNA polymerase eta (Polη) is the only translesion synthesis polymerase capable of error-free bypass of UV-induced cyclobutane pyrimidine dimers. A deficiency in Polη function is associated with the human disease Xeroderma pigmentosum variant (XPV). We ... ...

    Abstract DNA polymerase eta (Polη) is the only translesion synthesis polymerase capable of error-free bypass of UV-induced cyclobutane pyrimidine dimers. A deficiency in Polη function is associated with the human disease Xeroderma pigmentosum variant (XPV). We hereby report the case of a 60-year-old woman known for XPV and carrying a Polη Thr191Pro variant in homozygosity. We further characterize the variant in vitro and in vivo, providing molecular evidence that the substitution abrogates polymerase activity and results in UV sensitivity through deficient damage bypass. This is the first functional molecular characterization of a missense variant of Polη, whose reported pathogenic variants have thus far been loss of function truncation or frameshift mutations. Our work allows the upgrading of Polη Thr191Pro from 'variant of uncertain significance' to 'likely pathogenic mutant', bearing direct impact on molecular diagnosis and genetic counseling. Furthermore, we have established a robust experimental approach that will allow a precise molecular analysis of further missense mutations possibly linked to XPV. Finally, it provides insight into critical Polη residues that may be targeted to develop small molecule inhibitors for cancer therapeutics.
    MeSH term(s) Humans ; Middle Aged ; DNA Damage ; Mutation, Missense ; Proline/genetics ; Pyrimidine Dimers ; Ultraviolet Rays ; Xeroderma Pigmentosum/genetics ; Xeroderma Pigmentosum/pathology ; Female
    Chemical Substances Proline (9DLQ4CIU6V) ; Pyrimidine Dimers
    Language English
    Publishing date 2024-01-11
    Publishing country England
    Document type Case Reports ; Journal Article
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-023-51120-1
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: Remodeling Collapsed DNA Replication Forks for Cancer Development.

    Sotiriou, Sotirios K / Halazonetis, Thanos D

    Cancer research

    2019  Volume 79, Issue 7, Page(s) 1297–1298

    Abstract: DNA replication stress is prevalent in human cancers, but absent in normal cells, suggesting that proteins involved in the cellular response to DNA replication stress could be potential therapeutic targets. SMARCAL1 and ZRANB3 are annealing helicases ... ...

    Abstract DNA replication stress is prevalent in human cancers, but absent in normal cells, suggesting that proteins involved in the cellular response to DNA replication stress could be potential therapeutic targets. SMARCAL1 and ZRANB3 are annealing helicases that mediate the repair of collapsed DNA replication forks. In a study in this issue of
    MeSH term(s) Animals ; DNA Helicases/genetics ; DNA Replication ; Humans ; Mice
    Chemical Substances SMARCAL1 protein, human (EC 2.7.7.-) ; DNA Helicases (EC 3.6.4.-) ; ZRANB3 protein, human (EC 3.6.4.-)
    Language English
    Publishing date 2019-02-06
    Publishing country United States
    Document type Journal Article ; Comment
    ZDB-ID 1432-1
    ISSN 1538-7445 ; 0008-5472
    ISSN (online) 1538-7445
    ISSN 0008-5472
    DOI 10.1158/0008-5472.CAN-19-0216
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    Uh III Zs.135/5: Show issues Location:
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    bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular
    ab Jg. 2022: Lesesaal (EG)

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  8. Article ; Online: Transcription-replication conflicts underlie sensitivity to PARP inhibitors.

    Petropoulos, Michalis / Karamichali, Angeliki / Rossetti, Giacomo G / Freudenmann, Alena / Iacovino, Luca G / Dionellis, Vasilis S / Sotiriou, Sotirios K / Halazonetis, Thanos D

    Nature

    2024  Volume 628, Issue 8007, Page(s) 433–441

    Abstract: An important advance in cancer therapy has been the development of poly(ADP-ribose) polymerase (PARP) inhibitors for the treatment of homologous recombination (HR)-deficient ... ...

    Abstract An important advance in cancer therapy has been the development of poly(ADP-ribose) polymerase (PARP) inhibitors for the treatment of homologous recombination (HR)-deficient cancers
    MeSH term(s) Humans ; DNA Breaks, Double-Stranded ; DNA Replication/drug effects ; Poly(ADP-ribose) Polymerase Inhibitors/pharmacology ; Poly(ADP-ribose) Polymerases/metabolism ; Recombinational DNA Repair ; S Phase ; Transcription, Genetic/drug effects ; Neoplasms/drug therapy ; Neoplasms/pathology ; Poly (ADP-Ribose) Polymerase-1/metabolism
    Chemical Substances DNA synthesome (EC 2.7.7.-) ; PARP1 protein, human (EC 2.4.2.30) ; Poly(ADP-ribose) Polymerase Inhibitors ; Poly(ADP-ribose) Polymerases (EC 2.4.2.30) ; TIMELESS protein, human ; Tipin protein, human ; Poly (ADP-Ribose) Polymerase-1 (EC 2.4.2.30)
    Language English
    Publishing date 2024-03-20
    Publishing country England
    Document type Journal Article
    ZDB-ID 120714-3
    ISSN 1476-4687 ; 0028-0836
    ISSN (online) 1476-4687
    ISSN 0028-0836
    DOI 10.1038/s41586-024-07217-2
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 26: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
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    Jg. 1995 - 2021: Lesesall (1.OG)
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    Zs.MG 9: Show issues
    Zs.MO 244: Show issues

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  9. Article ; Online: Conservative DNA replication.

    Halazonetis, Thanos D

    Nature reviews. Molecular cell biology

    2014  Volume 15, Issue 5, Page(s) 300

    MeSH term(s) DNA Replication ; DNA, Fungal/genetics ; DNA, Fungal/metabolism ; Homologous Recombination ; Nucleic Acid Conformation ; Saccharomyces cerevisiae/genetics ; Saccharomyces cerevisiae/metabolism
    Chemical Substances DNA, Fungal
    Language English
    Publishing date 2014-03-26
    Publishing country England
    Document type Journal Article
    ZDB-ID 2031313-5
    ISSN 1471-0080 ; 1471-0072
    ISSN (online) 1471-0080
    ISSN 1471-0072
    DOI 10.1038/nrm3784
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 5446: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
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    Zs.MG 26: Show issues

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  10. Article ; Online: Monitoring early S-phase origin firing and replication fork movement by sequencing nascent DNA from synchronized cells.

    Macheret, Morgane / Halazonetis, Thanos D

    Nature protocols

    2018  Volume 14, Issue 1, Page(s) 51–67

    Abstract: A better understanding of DNA replication initiation in human cells and how this process is altered upon DNA replication stress requires the ability to study origin firing genome wide. Previously described methods of mapping DNA replication origins in ... ...

    Abstract A better understanding of DNA replication initiation in human cells and how this process is altered upon DNA replication stress requires the ability to study origin firing genome wide. Previously described methods of mapping DNA replication origins in higher eukaryotes rely principally on fractionation of DNA fragments based on their size and, optionally, on the presence of ribonucleotides at their 5' end. Here, we describe a protocol for EdUseq-HU, a method for mapping early S-phase replication origins. Cells, synchronized by mitotic shake-off, are released in medium containing 5-ethynyl-2'-deoxyuridine (EdU; to label nascent DNA) and hydroxyurea (HU; to limit fork progression after origin firing). After using click chemistry to tag the EdU label with a biotin conjugate that is cleavable under mild conditions, the nascent DNA is captured on streptavidin beads. One variant of EdUseq-HU allows mapping of DNA replication origins on the genome at a resolution of 10 kb, and a second variant monitors progression of replication forks. Using EdUseq-HU, the spatiotemporal program of DNA replication in human cell lines can be interrogated in <2 weeks. The protocol requires basic cell culture and molecular biology skills, as well as familiarity with the Perl programming language and the Linux operating system.
    MeSH term(s) Biotin/chemistry ; Cell Cycle Checkpoints/drug effects ; Cell Cycle Checkpoints/genetics ; Cell Line, Tumor ; Click Chemistry/methods ; DNA/genetics ; DNA/metabolism ; DNA Replication/drug effects ; Deoxyuridine/analogs & derivatives ; Deoxyuridine/pharmacology ; Genome, Human ; HeLa Cells ; Humans ; Hydroxyurea/pharmacology ; Molecular Probe Techniques ; Osteoblasts/cytology ; Osteoblasts/drug effects ; Osteoblasts/metabolism ; Replication Origin ; Software ; Streptavidin/chemistry
    Chemical Substances Biotin (6SO6U10H04) ; DNA (9007-49-2) ; Streptavidin (9013-20-1) ; 5-ethynyl-2'-deoxyuridine (G373S00W2J) ; Deoxyuridine (W78I7AY22C) ; Hydroxyurea (X6Q56QN5QC)
    Language English
    Publishing date 2018-11-28
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2244966-8
    ISSN 1750-2799 ; 1754-2189
    ISSN (online) 1750-2799
    ISSN 1754-2189
    DOI 10.1038/s41596-018-0081-y
    Database MEDical Literature Analysis and Retrieval System OnLINE

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