The Caenorhabditis elegans Homolog of Gen1/Yen1 Resolvases Links DNA Damage Signaling to DNA Double-Strand Break Repair

Aymeric P. Bailly, Alasdair Freeman, Julie Hall, Anne-Cecile Declais, Arno Alpi, David M. J. Lilley, Shawn Ahmed, Anton Gartner (Lead / Corresponding author)

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    55 Citations (Scopus)

    Abstract

    DNA double-strand breaks (DSBs) can be repaired by homologous recombination (HR), which can involve Holliday junction (HJ) intermediates that are ultimately resolved by nucleolytic enzymes. An N-terminal fragment of human GEN1 has recently been shown to act as a Holliday junction resolvase, but little is known about the role of GEN-1 in vivo. Holliday junction resolution signifies the completion of DNA repair, a step that may be coupled to signaling proteins that regulate cell cycle progression in response to DNA damage. Using forward genetic approaches, we identified a Caenorhabditis elegans dual function DNA double-strand break repair and DNA damage signaling protein orthologous to the human GEN1 Holliday junction resolving enzyme. GEN-1 has biochemical activities related to the human enzyme and facilitates repair of DNA double-strand breaks, but is not essential for DNA double-strand break repair during meiotic recombination. Mutational analysis reveals that the DNA damage-signaling function of GEN-1 is separable from its role in DNA repair. GEN-1 promotes germ cell cycle arrest and apoptosis via a pathway that acts in parallel to the canonical DNA damage response pathway mediated by RPA loading, CHK1 activation, and CEP-1/p53-mediated apoptosis induction. Furthermore, GEN-1 acts redundantly with the 9-1-1 complex to ensure genome stability. Our study suggests that GEN-1 might act as a dual function Holliday junction resolvase that may coordinate DNA damage signaling with a late step in DNA double-strand break repair.

    Original languageEnglish
    Article numbere1001025
    Pages (from-to)-
    Number of pages16
    JournalPLoS Genetics
    Volume6
    Issue number7
    DOIs
    Publication statusPublished - Jul 2010

    Keywords

    • HOLLIDAY JUNCTION RESOLVASE
    • STRUCTURE-SPECIFIC NUCLEASES
    • NUCLEOTIDE EXCISION-REPAIR
    • CELL-CYCLE ARREST
    • C-ELEGANS
    • INDUCED APOPTOSIS
    • CHECKPOINT PROTEIN
    • GERM-LINE
    • SACCHAROMYCES-CEREVISIAE
    • TELOMERE REPLICATION

    Cite this

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    title = "The Caenorhabditis elegans Homolog of Gen1/Yen1 Resolvases Links DNA Damage Signaling to DNA Double-Strand Break Repair",
    abstract = "DNA double-strand breaks (DSBs) can be repaired by homologous recombination (HR), which can involve Holliday junction (HJ) intermediates that are ultimately resolved by nucleolytic enzymes. An N-terminal fragment of human GEN1 has recently been shown to act as a Holliday junction resolvase, but little is known about the role of GEN-1 in vivo. Holliday junction resolution signifies the completion of DNA repair, a step that may be coupled to signaling proteins that regulate cell cycle progression in response to DNA damage. Using forward genetic approaches, we identified a Caenorhabditis elegans dual function DNA double-strand break repair and DNA damage signaling protein orthologous to the human GEN1 Holliday junction resolving enzyme. GEN-1 has biochemical activities related to the human enzyme and facilitates repair of DNA double-strand breaks, but is not essential for DNA double-strand break repair during meiotic recombination. Mutational analysis reveals that the DNA damage-signaling function of GEN-1 is separable from its role in DNA repair. GEN-1 promotes germ cell cycle arrest and apoptosis via a pathway that acts in parallel to the canonical DNA damage response pathway mediated by RPA loading, CHK1 activation, and CEP-1/p53-mediated apoptosis induction. Furthermore, GEN-1 acts redundantly with the 9-1-1 complex to ensure genome stability. Our study suggests that GEN-1 might act as a dual function Holliday junction resolvase that may coordinate DNA damage signaling with a late step in DNA double-strand break repair.",
    keywords = "HOLLIDAY JUNCTION RESOLVASE, STRUCTURE-SPECIFIC NUCLEASES, NUCLEOTIDE EXCISION-REPAIR, CELL-CYCLE ARREST, C-ELEGANS, INDUCED APOPTOSIS, CHECKPOINT PROTEIN, GERM-LINE, SACCHAROMYCES-CEREVISIAE, TELOMERE REPLICATION",
    author = "Bailly, {Aymeric P.} and Alasdair Freeman and Julie Hall and Anne-Cecile Declais and Arno Alpi and Lilley, {David M. J.} and Shawn Ahmed and Anton Gartner",
    year = "2010",
    month = "7",
    doi = "10.1371/journal.pgen.1001025",
    language = "English",
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    journal = "PLoS Genetics",
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    T1 - The Caenorhabditis elegans Homolog of Gen1/Yen1 Resolvases Links DNA Damage Signaling to DNA Double-Strand Break Repair

    AU - Bailly, Aymeric P.

    AU - Freeman, Alasdair

    AU - Hall, Julie

    AU - Declais, Anne-Cecile

    AU - Alpi, Arno

    AU - Lilley, David M. J.

    AU - Ahmed, Shawn

    AU - Gartner, Anton

    PY - 2010/7

    Y1 - 2010/7

    N2 - DNA double-strand breaks (DSBs) can be repaired by homologous recombination (HR), which can involve Holliday junction (HJ) intermediates that are ultimately resolved by nucleolytic enzymes. An N-terminal fragment of human GEN1 has recently been shown to act as a Holliday junction resolvase, but little is known about the role of GEN-1 in vivo. Holliday junction resolution signifies the completion of DNA repair, a step that may be coupled to signaling proteins that regulate cell cycle progression in response to DNA damage. Using forward genetic approaches, we identified a Caenorhabditis elegans dual function DNA double-strand break repair and DNA damage signaling protein orthologous to the human GEN1 Holliday junction resolving enzyme. GEN-1 has biochemical activities related to the human enzyme and facilitates repair of DNA double-strand breaks, but is not essential for DNA double-strand break repair during meiotic recombination. Mutational analysis reveals that the DNA damage-signaling function of GEN-1 is separable from its role in DNA repair. GEN-1 promotes germ cell cycle arrest and apoptosis via a pathway that acts in parallel to the canonical DNA damage response pathway mediated by RPA loading, CHK1 activation, and CEP-1/p53-mediated apoptosis induction. Furthermore, GEN-1 acts redundantly with the 9-1-1 complex to ensure genome stability. Our study suggests that GEN-1 might act as a dual function Holliday junction resolvase that may coordinate DNA damage signaling with a late step in DNA double-strand break repair.

    AB - DNA double-strand breaks (DSBs) can be repaired by homologous recombination (HR), which can involve Holliday junction (HJ) intermediates that are ultimately resolved by nucleolytic enzymes. An N-terminal fragment of human GEN1 has recently been shown to act as a Holliday junction resolvase, but little is known about the role of GEN-1 in vivo. Holliday junction resolution signifies the completion of DNA repair, a step that may be coupled to signaling proteins that regulate cell cycle progression in response to DNA damage. Using forward genetic approaches, we identified a Caenorhabditis elegans dual function DNA double-strand break repair and DNA damage signaling protein orthologous to the human GEN1 Holliday junction resolving enzyme. GEN-1 has biochemical activities related to the human enzyme and facilitates repair of DNA double-strand breaks, but is not essential for DNA double-strand break repair during meiotic recombination. Mutational analysis reveals that the DNA damage-signaling function of GEN-1 is separable from its role in DNA repair. GEN-1 promotes germ cell cycle arrest and apoptosis via a pathway that acts in parallel to the canonical DNA damage response pathway mediated by RPA loading, CHK1 activation, and CEP-1/p53-mediated apoptosis induction. Furthermore, GEN-1 acts redundantly with the 9-1-1 complex to ensure genome stability. Our study suggests that GEN-1 might act as a dual function Holliday junction resolvase that may coordinate DNA damage signaling with a late step in DNA double-strand break repair.

    KW - HOLLIDAY JUNCTION RESOLVASE

    KW - STRUCTURE-SPECIFIC NUCLEASES

    KW - NUCLEOTIDE EXCISION-REPAIR

    KW - CELL-CYCLE ARREST

    KW - C-ELEGANS

    KW - INDUCED APOPTOSIS

    KW - CHECKPOINT PROTEIN

    KW - GERM-LINE

    KW - SACCHAROMYCES-CEREVISIAE

    KW - TELOMERE REPLICATION

    U2 - 10.1371/journal.pgen.1001025

    DO - 10.1371/journal.pgen.1001025

    M3 - Article

    VL - 6

    SP - -

    JO - PLoS Genetics

    JF - PLoS Genetics

    SN - 1553-7390

    IS - 7

    M1 - e1001025

    ER -