title: Human LIGIV is synthetically lethal with the loss of Rad54B-dependent recombination and is required for certain chromosome fusion events induced by telomere dysfunction.
abstract: Classic non-homologous end joining (C-NHEJ) is the predominant DNA double-strand break repair pathway in humans. Although seven genes Ku70, Ku86, DNA-PK(cs), Artemis, DNA Ligase IV (LIGIV), X-ray cross-complementing group 4 and XRCC4-like factor are required for C-NHEJ, several of them also have ancillary functions. For example, Ku70:Ku86 possesses an essential telomere maintenance activity. In contrast, LIGIV is believed to function exclusively in C-NHEJ. Moreover, a viable LIGIV-null human B-cell line and LIGIV-reduced patient cell lines have been described. Together, these observations suggest that LIGIV (and hence C-NHEJ), albeit important, is nonetheless dispensable, whereas Ku70:Ku86 and telomere maintenance are essential. To confirm this hypothesis, we inactivated LIGIV in the epithelial human cell line, HCT116. The resulting LIGIV-null cell line was viable, verifying that the gene and C-NHEJ are not essential. However, functional inactivation of RAD54B, a key homologous recombination factor, in the LIGIV-null background yielded no viable clones, suggesting that the combined absence of RAD54B/homologous recombination and C-NHEJ is synthetically lethal. Finally, we demonstrate that LIGIV is differentially required for certain chromosome fusion events induced by telomere dysfunction-used for those owing to the overexpression of a dominant negative version of telomere recognition factor 2, but not used for those owing to absence of Ku70:Ku86.
authors.affiliation: Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
authors.forename: Sehyun
authors.initials: S
authors.lastname: Oh
authors.forename: Yongbao
authors.initials: Y
authors.lastname: Wang
authors.forename: Jacob
authors.initials: J
authors.lastname: Zimbric
authors.forename: Eric A
authors.initials: EA
authors.lastname: Hendrickson
mesh_terms: D034961:Antigens, Nuclear / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002842:Chromatids; D002869:Chromosome Aberrations; D004249:DNA Damage; D059766:DNA End-Joining Repair; D004265:DNA Helicases / Q000235:genetics*; D000072481:DNA Ligase ATP; D011088:DNA Ligases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000235:genetics; D018390:Gene Targeting; D042822:Genomic Instability; D006801:Humans; D000072200:Ku Autoantigen; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*; D011995:Recombination, Genetic; D059767:Recombinational DNA Repair; D016615:Telomere / Q000502:physiology*; D059505:Telomere Homeostasis; D035341:Telomeric Repeat Binding Protein 2 / Q000378:metabolism
chemical_list: D034961:Antigens, Nuclear; D004268:DNA-Binding Proteins; C000607893:LIG4 protein, human; D009687:Nuclear Proteins; C491221:RAD54B protein, human; D035341:Telomeric Repeat Binding Protein 2; D004265:DNA Helicases; C000606509:Xrcc6 protein, human; D000072200:Ku Autoantigen; D011088:DNA Ligases; D000072481:DNA Ligase ATP