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

• DOI: 10.1038/nsmb1313
• Publication Date: 2007-10-14T17:40:28Z
• Authors: Katsuhiro Hanada; Magda Budzowska; Sally L Davies; Ellen van Drunen; Hideo Onizawa; H Berna Beverloo; Alex Maas; Jeroen Essers; Ian D Hickson; Roland Kanaar
• Keywords: DNA Replication; 0301 basic medicine; Mice; 03 medical and health sciences; Aphidicolin; Chromosomal Instability; Animals; Humans; Hydroxyurea; DNA Breaks, Double-Stranded; Enzyme Inhibitors; EMC MGC-02-96-01; Cells, Cultured; Embryonic Stem Cells; Chromosome Aberrations; Mice, Knockout; Cell Cycle; DNA Helicases; Nuclear Proteins; Endonucleases; Chromosomes, Mammalian; 3. Good health; EMC MM-03-32-04; DNA-Binding Proteins; Nucleic Acid Conformation; EMC MGC-01-12-03

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.