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  1. Article ; Online: Extraordinary collateral mutagenesis induced by CX-5461.

    Boulton, Simon J

    Nature genetics

    2023  Volume 56, Issue 1, Page(s) 12–13

    MeSH term(s) Mutagenesis/genetics ; Benzothiazoles ; Naphthyridines
    Chemical Substances CX 5461 ; Benzothiazoles ; Naphthyridines
    Language English
    Publishing date 2023-12-22
    Publishing country United States
    Document type Journal Article
    ZDB-ID 1108734-1
    ISSN 1546-1718 ; 1061-4036
    ISSN (online) 1546-1718
    ISSN 1061-4036
    DOI 10.1038/s41588-023-01611-8
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Micronuclei induced by radiation, replication stress, or chromosome segregation errors do not activate cGAS-STING.

    Takaki, Tohru / Millar, Rhona / Hiley, Crispin T / Boulton, Simon J

    Molecular cell

    2024  

    Abstract: The cyclic guanosine monophosphate (GMP)-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway plays a pivotal role in innate immune responses to viral infection and inhibition of autoimmunity. Recent studies have suggested that micronuclei ... ...

    Abstract The cyclic guanosine monophosphate (GMP)-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway plays a pivotal role in innate immune responses to viral infection and inhibition of autoimmunity. Recent studies have suggested that micronuclei formed by genotoxic stress can activate innate immune signaling via the cGAS-STING pathway. Here, we investigated cGAS localization, activation, and downstream signaling from micronuclei induced by ionizing radiation, replication stress, and chromosome segregation errors. Although cGAS localized to ruptured micronuclei via binding to self-DNA, we failed to observe cGAS activation; cGAMP production; downstream phosphorylation of STING, TBK1, or IRF3; nuclear accumulation of IRF3; or expression of interferon-stimulated genes. Failure to activate the cGAS-STING pathway was observed across primary and immortalized cell lines, which retained the ability to activate the cGAS-STING pathway in response to dsDNA or modified vaccinia virus infection. We provide evidence that micronuclei formed by genotoxic insults contain histone-bound self-DNA, which we show is inhibitory to cGAS activation in cells.
    Language English
    Publishing date 2024-05-09
    Publishing country United States
    Document type Journal Article
    ZDB-ID 1415236-8
    ISSN 1097-4164 ; 1097-2765
    ISSN (online) 1097-4164
    ISSN 1097-2765
    DOI 10.1016/j.molcel.2024.04.017
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: The end protection problem-an unexpected twist in the tail.

    Ruis, Phil / Boulton, Simon J

    Genes & development

    2020  Volume 35, Issue 1-2, Page(s) 1–21

    Abstract: In this perspective, we introduce shelterin and the mechanisms of ATM activation and NHEJ at telomeres, before discussing the following questions: How are t-loops proposed to protect chromosome ends and what is the evidence for this model? Can other ... ...

    Abstract In this perspective, we introduce shelterin and the mechanisms of ATM activation and NHEJ at telomeres, before discussing the following questions: How are t-loops proposed to protect chromosome ends and what is the evidence for this model? Can other models explain how TRF2 mediates end protection? Could t-loops be pathological structures? How is end protection achieved in pluripotent cells? What do the insights into telomere end protection in pluripotent cells mean for the t-loop model of end protection? Why might different cell states have evolved different mechanisms of end protection? Finally, we offer support for an updated t-loop model of end protection, suggesting that the data is supportive of a critical role for t-loops in protecting chromosome ends from NHEJ and ATM activation, but that other mechanisms are involved. Finally, we propose that t-loops are likely dynamic, rather than static, structures.
    MeSH term(s) Animals ; Ataxia Telangiectasia Mutated Proteins/metabolism ; Chromosomal Instability ; DNA Breaks, Double-Stranded ; DNA End-Joining Repair/physiology ; DNA Repair ; Embryonic Stem Cells ; Humans ; Models, Biological ; Pluripotent Stem Cells ; Telomere/metabolism ; Telomere/pathology ; Telomeric Repeat Binding Protein 2/metabolism
    Chemical Substances Telomeric Repeat Binding Protein 2 ; Ataxia Telangiectasia Mutated Proteins (EC 2.7.11.1)
    Language English
    Publishing date 2020-12-23
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 806684-x
    ISSN 1549-5477 ; 0890-9369
    ISSN (online) 1549-5477
    ISSN 0890-9369
    DOI 10.1101/gad.344044.120
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article: Spotlight on the Replisome: Aetiology of DNA Replication-Associated Genetic Diseases.

    Bellelli, Roberto / Boulton, Simon J

    Trends in genetics : TIG

    2020  Volume 37, Issue 4, Page(s) 317–336

    Abstract: Human development and tissue homeostasis depend on the regulated control of cellular proliferation and differentiation. DNA replication is essential to couple genome duplication and cell division with the establishment and maintenance of cellular ... ...

    Abstract Human development and tissue homeostasis depend on the regulated control of cellular proliferation and differentiation. DNA replication is essential to couple genome duplication and cell division with the establishment and maintenance of cellular differentiation programs. In eukaryotes, DNA replication is performed by a large machine known as the 'replisome,' which is strictly regulated in a cell cycle-dependent manner. Inherited mutations of replisome components have been identified in a range of genetic conditions characterised by developmental abnormalities and reduced organismal growth in addition to an involvement of the immune and endocrine systems and/or heightened tumour predisposition. Here, we review the current knowledge of the molecular genetics of replisome dysfunction disorders and discuss recent mechanistic insights into their pathogenesis, with a focus on the specific steps of DNA replication affected in these human diseases.
    MeSH term(s) Cell Cycle/genetics ; Cell Differentiation/genetics ; Cell Proliferation/genetics ; DNA Replication/genetics ; Genetic Diseases, Inborn/etiology ; Genetic Diseases, Inborn/genetics ; Humans ; Multiprotein Complexes/genetics ; Mutation/genetics ; Whole Genome Sequencing
    Chemical Substances Multiprotein Complexes
    Language English
    Publishing date 2020-10-08
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 619240-3
    ISSN 1362-4555 ; 0168-9525 ; 0168-9479
    ISSN (online) 1362-4555
    ISSN 0168-9525 ; 0168-9479
    DOI 10.1016/j.tig.2020.09.008
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Mechanism of mitotic recombination: insights from C. elegans.

    Belan, Ondrej / Anand, Roopesh / Boulton, Simon J

    Current opinion in genetics & development

    2021  Volume 71, Page(s) 10–18

    Abstract: Homologous recombination (HR) plays a critical role in largely error-free repair of mitotic and meiotic DNA double-strand breaks (DSBs). DSBs are one of the most deleterious DNA lesions, which are repaired by non-homologous end joining (NHEJ), homologous ...

    Abstract Homologous recombination (HR) plays a critical role in largely error-free repair of mitotic and meiotic DNA double-strand breaks (DSBs). DSBs are one of the most deleterious DNA lesions, which are repaired by non-homologous end joining (NHEJ), homologous recombination (HR) or, if compromised, micro-homology mediated end joining (MMEJ). If left unrepaired, DSBs can lead to cell death or if repaired incorrectly can result in chromosome rearrangements that drive cancer development. Here, we describe recent advances in the field of mitotic HR made using Caenorhabditis elegans roundworm, as a model system.
    MeSH term(s) Animals ; Caenorhabditis elegans/genetics ; DNA Breaks, Double-Stranded ; DNA End-Joining Repair ; DNA Repair ; DNA Replication ; Homologous Recombination/genetics
    Language English
    Publishing date 2021-06-26
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 1077312-5
    ISSN 1879-0380 ; 0959-437X
    ISSN (online) 1879-0380
    ISSN 0959-437X
    DOI 10.1016/j.gde.2021.06.005
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Beyond PARP-POLθ as an anticancer target.

    Higgins, Geoff S / Boulton, Simon J

    Science (New York, N.Y.)

    2018  Volume 359, Issue 6381, Page(s) 1217–1218

    MeSH term(s) Antineoplastic Agents/therapeutic use ; DNA Breaks, Double-Stranded ; DNA End-Joining Repair ; DNA Repair-Deficiency Disorders/drug therapy ; DNA Repair-Deficiency Disorders/genetics ; DNA-Directed DNA Polymerase/metabolism ; Genes, BRCA1 ; Homologous Recombination ; Humans ; Molecular Targeted Therapy ; Neoplasms/drug therapy ; Neoplasms/genetics ; Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use ; Poly(ADP-ribose) Polymerases/metabolism ; DNA Polymerase theta
    Chemical Substances Antineoplastic Agents ; Poly(ADP-ribose) Polymerase Inhibitors ; Poly(ADP-ribose) Polymerases (EC 2.4.2.30) ; DNA-Directed DNA Polymerase (EC 2.7.7.7)
    Language English
    Publishing date 2018-03-27
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 128410-1
    ISSN 1095-9203 ; 0036-8075
    ISSN (online) 1095-9203
    ISSN 0036-8075
    DOI 10.1126/science.aar5149
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: New Editor-in-Chief-welcome to Simon Boulton!

    Nigg, Erich A / Boulton, Simon J

    Chromosoma

    2018  Volume 127, Issue 1, Page(s) 1

    Language English
    Publishing date 2018-01-29
    Publishing country Austria
    Document type Editorial
    ZDB-ID 203083-4
    ISSN 1432-0886 ; 0009-5915
    ISSN (online) 1432-0886
    ISSN 0009-5915
    DOI 10.1007/s00412-018-0661-1
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: Tackling PARP inhibitor resistance.

    Fugger, Kasper / Hewitt, Graeme / West, Stephen C / Boulton, Simon J

    Trends in cancer

    2021  Volume 7, Issue 12, Page(s) 1102–1118

    Abstract: Homologous recombination-deficient (HRD) tumours, including those harbouring mutations in the BRCA genes, are hypersensitive to treatment with inhibitors of poly(ADP-ribose) polymerase (PARPis). Despite high response rates, most HRD cancers ultimately ... ...

    Abstract Homologous recombination-deficient (HRD) tumours, including those harbouring mutations in the BRCA genes, are hypersensitive to treatment with inhibitors of poly(ADP-ribose) polymerase (PARPis). Despite high response rates, most HRD cancers ultimately develop resistance to PARPi treatment through reversion mutations or genetic/epigenetic alterations to DNA repair pathways. Counteracting these resistance pathways, thereby increasing the potency of PARPi therapy, represents a potential strategy to improve the treatment of HRD cancers. In this review, we discuss recent insights derived from genetic screens that have identified a number of novel genes that can be targeted to improve PARPi treatment of HRD cancers and may provide a means to overcome PARPi resistance.
    MeSH term(s) Antineoplastic Agents/therapeutic use ; Drug Resistance, Neoplasm ; Female ; Genes, Tumor Suppressor ; Homologous Recombination/genetics ; Humans ; Ovarian Neoplasms/drug therapy ; Poly(ADP-ribose) Polymerase Inhibitors/pharmacology ; Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use
    Chemical Substances Antineoplastic Agents ; Poly(ADP-ribose) Polymerase Inhibitors
    Language English
    Publishing date 2021-09-22
    Publishing country United States
    Document type Journal Article ; Review
    ZDB-ID 2852626-0
    ISSN 2405-8025 ; 2405-8033 ; 2405-8033
    ISSN (online) 2405-8025 ; 2405-8033
    ISSN 2405-8033
    DOI 10.1016/j.trecan.2021.08.007
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article ; Online: Differential regulation of the PIKK kinase family by Tel2.

    Boulton, Simon J

    Cell cycle (Georgetown, Tex.)

    2011  Volume 7, Issue 23, Page(s) 3617

    MeSH term(s) Animals ; Enzyme Stability ; Mice ; Protein Binding ; Protein-Serine-Threonine Kinases/metabolism ; Saccharomyces cerevisiae/enzymology ; Telomere-Binding Proteins/metabolism
    Chemical Substances Telomere-Binding Proteins ; Protein-Serine-Threonine Kinases (EC 2.7.11.1)
    Language English
    Publishing date 2011-03-10
    Publishing country United States
    Document type News
    ZDB-ID 2146183-1
    ISSN 1551-4005 ; 1538-4101 ; 1554-8627
    ISSN (online) 1551-4005
    ISSN 1538-4101 ; 1554-8627
    DOI 10.4161/cc.7.23.7430
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  10. Article ; Online: Nucleotide proofreading functions by nematode RAD51 paralogs facilitate optimal RAD51 filament function.

    Špírek, Mário / Taylor, Martin R G / Belan, Ondrej / Boulton, Simon J / Krejci, Lumir

    Nature communications

    2021  Volume 12, Issue 1, Page(s) 5545

    Abstract: The RAD51 recombinase assembles as helical nucleoprotein filaments on single-stranded DNA (ssDNA) and mediates invasion and strand exchange with homologous duplex DNA (dsDNA) during homologous recombination (HR), as well as protection and restart of ... ...

    Abstract The RAD51 recombinase assembles as helical nucleoprotein filaments on single-stranded DNA (ssDNA) and mediates invasion and strand exchange with homologous duplex DNA (dsDNA) during homologous recombination (HR), as well as protection and restart of stalled replication forks. Strand invasion by RAD51-ssDNA complexes depends on ATP binding. However, RAD51 can bind ssDNA in non-productive ADP-bound or nucleotide-free states, and ATP-RAD51-ssDNA complexes hydrolyse ATP over time. Here, we define unappreciated mechanisms by which the RAD51 paralog complex RFS-1/RIP-1 limits the accumulation of RAD-51-ssDNA complexes with unfavorable nucleotide content. We find RAD51 paralogs promote the turnover of ADP-bound RAD-51 from ssDNA, in striking contrast to their ability to stabilize productive ATP-bound RAD-51 nucleoprotein filaments. In addition, RFS-1/RIP-1 inhibits binding of nucleotide-free RAD-51 to ssDNA. We propose that 'nucleotide proofreading' activities of RAD51 paralogs co-operate to ensure the enrichment of active, ATP-bound RAD-51 filaments on ssDNA to promote HR.
    MeSH term(s) Adenosine Diphosphate/pharmacology ; Adenosine Triphosphate/pharmacology ; Animals ; Caenorhabditis elegans/metabolism ; Caenorhabditis elegans Proteins/metabolism ; DNA, Single-Stranded/metabolism ; Fluorescence ; Interferometry ; Nucleotides/metabolism ; Protein Binding/drug effects ; Protein Stability/drug effects ; Rad51 Recombinase/chemistry ; Rad51 Recombinase/metabolism ; Sequence Homology, Amino Acid ; Species Specificity
    Chemical Substances Caenorhabditis elegans Proteins ; DNA, Single-Stranded ; Nucleotides ; Adenosine Diphosphate (61D2G4IYVH) ; Adenosine Triphosphate (8L70Q75FXE) ; Rad51 Recombinase (EC 2.7.7.-)
    Language English
    Publishing date 2021-09-20
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-021-25830-x
    Database MEDical Literature Analysis and Retrieval System OnLINE

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