title: Homologous and non-homologous recombination differentially affect DNA damage repair in mice.
abstract: Ionizing radiation and interstrand DNA crosslinking compounds provide important treatments against cancer due to their extreme genotoxicity for proliferating cells. Both the efficacies of such treatments and the mutagenic potential of these agents are modulated by the ability of cells to repair the inflicted DNA damage. Here we demonstrate that homologous recombination-deficient mRAD54(-/-) mice are hypersensitive to ionizing radiation at the embryonic but, unexpectedly, not at the adult stage. However, at the adult stage mRAD54 deficiency dramatically aggravates the ionizing radiation sensitivity of severe combined immune deficiency (scid) mice that are impaired in DNA double-strand break repair through DNA end-joining. In contrast, regardless of developmental stage, mRAD54(-/-) mice are hypersensitive to the interstrand DNA crosslinking compound mitomycin C. These results demonstrate that the two major DNA double-strand break repair pathways in mammals have overlapping as well as specialized roles, and that the relative contribution of these pathways towards repair of ionizing radiation-induced DNA damage changes during development of the animal.
authors.affiliation: Department of Cell Biology and Genetics, Erasmus University Rotterdam, PO Box 1738, 3000 DR Rotterdam.
authors.forename: J
authors.initials: J
authors.lastname: Essers
authors.forename: H
authors.initials: H
authors.lastname: van Steeg
authors.forename: J
authors.initials: J
authors.lastname: de Wit
authors.forename: S M
authors.initials: SM
authors.lastname: Swagemakers
authors.forename: M
authors.initials: M
authors.lastname: Vermeij
authors.forename: J H
authors.initials: JH
authors.lastname: Hoeijmakers
authors.forename: R
authors.initials: R
authors.lastname: Kanaar
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000187:drug effects / Q000473:pathology / Q000528:radiation effects; D004249:DNA Damage; D004260:DNA Repair / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016513:Mice, SCID; D016685:Mitomycin / Q000494:pharmacology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D011836:Radiation Tolerance / Q000235:genetics; D011995:Recombination, Genetic
chemical_list: D009687:Nuclear Proteins; D016685:Mitomycin