The structure-specific endonuclease Mus81 contributes to replication restart by generating double-strand DNA breaks

Nat Struct Mol Biol. 2007 Nov;14(11):1096-104. doi: 10.1038/nsmb1313. Epub 2007 Oct 14.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aphidicolin / pharmacology
  • Cell Cycle / physiology
  • Cells, Cultured
  • Chromosomal Instability
  • Chromosome Aberrations / chemically induced
  • Chromosomes, Mammalian / chemistry*
  • Chromosomes, Mammalian / genetics
  • Chromosomes, Mammalian / metabolism*
  • DNA Breaks, Double-Stranded*
  • DNA Helicases
  • DNA Replication*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Embryonic Stem Cells / cytology
  • Embryonic Stem Cells / drug effects
  • Embryonic Stem Cells / physiology
  • Embryonic Stem Cells / radiation effects
  • Endonucleases / genetics
  • Endonucleases / metabolism*
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Hydroxyurea / pharmacology
  • Mice
  • Mice, Knockout
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Nucleic Acid Conformation*
  • Nucleic Acid Synthesis Inhibitors / pharmacology
  • Rad51 Recombinase / genetics
  • Rad51 Recombinase / metabolism
  • Radiation, Ionizing


  • DNA-Binding Proteins
  • Enzyme Inhibitors
  • Nuclear Proteins
  • Nucleic Acid Synthesis Inhibitors
  • Aphidicolin
  • Rad51 Recombinase
  • Rad51 protein, mouse
  • Endonucleases
  • Mus81 protein, mouse
  • DNA Helicases
  • Rad54l protein, mouse
  • Hydroxyurea