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.
authors.affiliation: Wellcome Trust Centre for Gene Regulation and Expression, University of Dundee, Dundee, United Kingdom.
authors.forename: Aymeric P
authors.initials: AP
authors.lastname: Bailly
authors.forename: Alasdair
authors.initials: A
authors.lastname: Freeman
authors.forename: Julie
authors.initials: J
authors.lastname: Hall
authors.forename: Anne-Cécile
authors.initials: AC
authors.lastname: Déclais
authors.forename: Arno
authors.initials: A
authors.lastname: Alpi
authors.forename: David M J
authors.initials: DM
authors.lastname: Lilley
authors.forename: Shawn
authors.initials: S
authors.lastname: Ahmed
authors.forename: Anton
authors.initials: A
authors.lastname: Gartner
mesh_terms: D000818:Animals; D017209:Apoptosis; D017173:Caenorhabditis elegans / Q000235:genetics*; D002453:Cell Cycle; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage; D004260:DNA Repair; D042822:Genomic Instability; D005854:Germ Cells; D045565:Holliday Junction Resolvases / Q000235:genetics / Q000502:physiology*; D008540:Meiosis; D015398:Signal Transduction / Q000235:genetics
chemical_list: C533748:GEN1 protein, human; D045565:Holliday Junction Resolvases