title: The nonhomologous end-joining pathway of DNA repair is required for genomic stability and the suppression of translocations.
abstract: We have used spectral karyotyping to assess potential roles of three different components of the nonhomologous DNA end-joining pathway in the maintenance of genomic stability in mouse embryonic fibroblasts (MEFs). MEFs homozygous for mutations that inactivate either DNA ligase IV (Lig4) or Ku70 display dramatic genomic instability, even in the absence of exogenous DNA damaging agents. These aberrant events range from chromosomal fragmentation to nonreciprocal translocations that can involve several chromosomes. DNA-dependent protein kinase catalytic subunit deficiency also promotes genome instability. Deficiency for the p53 cell cycle checkpoint protein has little effect on spontaneous levels of chromosomal instability in Lig4-deficient fibroblasts. However, in the context of ionizing radiation treatment, p53 deficiency allowed visualization of massive acute chromosomal destruction in Lig4-deficient MEFs, which in surviving cells manifested as frequent nonreciprocal translocations. We conclude that nonhomologous DNA end-joining plays a crucial role as a caretaker of the mammalian genome, and that an alternative repair pathway exists that often leads to nonreciprocal translocations.
authors.affiliation: Howard Hughes Medical Institute, The Children's Hospital, The Center for Blood Research, Boston, MA 02115, USA.
authors.forename: D O
authors.initials: DO
authors.lastname: Ferguson
authors.forename: J M
authors.initials: JM
authors.lastname: Sekiguchi
authors.forename: S
authors.initials: S
authors.lastname: Chang
authors.forename: K M
authors.initials: KM
authors.lastname: Frank
authors.forename: Y
authors.initials: Y
authors.lastname: Gao
authors.forename: R A
authors.initials: RA
authors.lastname: DePinho
authors.forename: F W
authors.initials: FW
authors.lastname: Alt
mesh_terms: D000818:Animals; D002869:Chromosome Aberrations; D004260:DNA Repair; D051379:Mice; D014178:Translocation, Genetic