title: Rad54 and DNA Ligase IV cooperate to maintain mammalian chromatid stability.
abstract: Nonhomologous end joining (NHEJ) and homologous recombination (HR) represent the two major pathways of DNA double-strand break (DSB) repair in eukaryotic cells. NHEJ repairs DSBs by ligation of cognate broken ends irrespective of homologous flanking sequences, whereas HR repairs DSBs using an undamaged homologous template. Although both NHEJ and HR have been clearly implicated in the maintenance of genome stability, how these apparently independent and mechanistically distinct pathways are coordinated remains largely unexplored. To investigate the relationship between HR and NHEJ modes of DSB repair, we generated cells doubly deficient for the NHEJ factor DNA Ligase IV (Lig4) and the HR factor Rad54. We show that Lig4 and Rad54 cooperate to support cellular proliferation, repair spontaneous DSBs, and prevent chromosome and single chromatid aberrations. These findings demonstrate a role for NHEJ in the repair of DSBs that occur spontaneously during or after DNA replication, and reveal overlapping functions for NHEJ and Rad54-dependent HR in the repair of such DSBs.
authors.affiliation: CBR Institute for Biomedical Research, Boston, Massachusetts 02115, USA.
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Mills
authors.forename: David O
authors.initials: DO
authors.lastname: Ferguson
authors.forename: Jeroen
authors.initials: J
authors.lastname: Essers
authors.forename: Mark
authors.initials: M
authors.lastname: Eckersdorff
authors.forename: Roland
authors.initials: R
authors.lastname: Kanaar
authors.forename: Frederick W
authors.initials: FW
authors.lastname: Alt
mesh_terms: D000818:Animals; D001921:Brain / Q000473:pathology; D002455:Cell Division / Q000235:genetics; D002478:Cells, Cultured; D002842:Chromatids / Q000235:genetics*; D002869:Chromosome Aberrations; D004247:DNA / Q000235:genetics / Q000378:metabolism; D004265:DNA Helicases; D000072481:DNA Ligase ATP; D011088:DNA Ligases / Q000235:genetics / Q000378:metabolism*; D004260:DNA Repair / Q000502:physiology; D005298:Fertility / Q000235:genetics; D005347:Fibroblasts; D008322:Mammals / Q000235:genetics; D051379:Mice; D008817:Mice, Mutant Strains; D009474:Neurons / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011995:Recombination, Genetic; D012854:Sister Chromatid Exchange
chemical_list: D009687:Nuclear Proteins; D004247:DNA; D004265:DNA Helicases; C103534:Rad54l protein, mouse; D011088:DNA Ligases; D000072481:DNA Ligase ATP