title: The structure-specific endonuclease Mus81 contributes to replication restart by generating double-strand DNA breaks.
abstract: Faithful duplication of the genome requires structure-specific endonucleases such as the RuvABC complex in Escherichia coli. These enzymes help to resolve problems at replication forks that have been disrupted by DNA damage in the template. Much less is known about the identities of these enzymes in mammalian cells. Mus81 is the catalytic component of a eukaryotic structure-specific endonuclease that preferentially cleaves branched DNA substrates reminiscent of replication and recombination intermediates. Here we explore the mechanisms by which Mus81 maintains chromosomal stability. We found that Mus81 is involved in the formation of double-strand DNA breaks in response to the inhibition of replication. Moreover, in the absence of chromosome processing by Mus81, recovery of stalled DNA replication forks is attenuated and chromosomal aberrations arise. We suggest that Mus81 suppresses chromosomal instability by converting potentially detrimental replication-associated DNA structures into intermediates that are more amenable to DNA repair.
authors.affiliation: Department of Cell Biology & Genetics, Erasmus Medical Center, PO Box 2040, 3000 CA Rotterdam, The Netherlands.
authors.forename: Katsuhiro
authors.initials: K
authors.lastname: Hanada
authors.forename: Magda
authors.initials: M
authors.lastname: Budzowska
authors.forename: Sally L
authors.initials: SL
authors.lastname: Davies
authors.forename: Ellen
authors.initials: E
authors.lastname: van Drunen
authors.forename: Hideo
authors.initials: H
authors.lastname: Onizawa
authors.forename: H Berna
authors.initials: HB
authors.lastname: Beverloo
authors.forename: Alex
authors.initials: A
authors.lastname: Maas
authors.forename: Jeroen
authors.initials: J
authors.lastname: Essers
authors.forename: Ian D
authors.initials: ID
authors.lastname: Hickson
authors.forename: Roland
authors.initials: R
authors.lastname: Kanaar
mesh_terms: D000818:Animals; D016590:Aphidicolin / Q000494:pharmacology; D002453:Cell Cycle / Q000502:physiology; D002478:Cells, Cultured; D043171:Chromosomal Instability; D002869:Chromosome Aberrations / Q000139:chemically induced; D033481:Chromosomes, Mammalian / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D053903:DNA Breaks, Double-Stranded; D004265:DNA Helicases; D004261:DNA Replication; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D053595:Embryonic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D004720:Endonucleases / Q000235:genetics / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D006918:Hydroxyurea / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D009690:Nucleic Acid Conformation; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D051135:Rad51 Recombinase / Q000235:genetics / Q000378:metabolism; D011839:Radiation, Ionizing
chemical_list: D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D009687:Nuclear Proteins; D019384:Nucleic Acid Synthesis Inhibitors; D016590:Aphidicolin; D051135:Rad51 Recombinase; C495154:Rad51 protein, mouse; D004720:Endonucleases; C498773:Mus81 protein, mouse; D004265:DNA Helicases; C103534:Rad54l protein, mouse; D006918:Hydroxyurea