Early embryonic lethality due to targeted inactivation of DNA ligase III.
DNA ligases catalyze the joining of strand breaks in the phosphodiester backbone of duplex DNA and play essential roles in DNA replication, recombination, repair, and maintenance of genomic integrity. Three mammalian DNA ligase genes have been identified, and their corresponding ligases play distinct roles in DNA metabolism. DNA ligase III is proposed to be involved in the repairing of DNA single-strand breaks, but its precise role has not yet been demonstrated directly. To determine its role in DNA repair, cellular growth, and embryonic development, we introduced targeted interruption of the DNA ligase III (LIG3) gene into the mouse. Mice homozygous for LIG3 disruption showed early embryonic lethality. We found that the mutant embryonic developmental process stops at 8.5 days postcoitum (dpc), and excessive cell death occurs at 9.5 dpc. LIG3 mutant cells have relatively normal XRCC1 levels but elevated sister chromatid exchange. These findings indicate that DNA ligase III is involved in essential DNA repair activities required for early embryonic development and therefore cannot be replaced by other DNA ligases.
Puebla-Osorio
Nahum
N
Department of Immunology, Unit 902, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, Texas 77030, USA.
Lacey
Devin B
DB
Alt
Frederick W
FW
Zhu
Chengming
C
D000818:Animals; D017209:Apoptosis; D015139:Blotting, Southern; D015153:Blotting, Western; D000072481:DNA Ligase ATP; D011088:DNA Ligases / Q000172:deficiency / Q000235:genetics* / Q000502:physiology*; D018274:Electroporation; D004622:Embryo, Mammalian / Q000201:enzymology* / Q000473:pathology; D005091:Exons; D005260:Female; D018390:Gene Targeting; D005804:Genes, Lethal; D006367:HeLa Cells; D006720:Homozygote; D006801:Humans; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D000075223:Poly-ADP-Ribose Binding Proteins; D016133:Polymerase Chain Reaction; D011247:Pregnancy; D034622:RNA Interference; D015183:Restriction Mapping; D012854:Sister Chromatid Exchange; D013234:Stem Cells / Q000166:cytology; D029867:Xenopus Proteins
D000075223:Poly-ADP-Ribose Binding Proteins; D029867:Xenopus Proteins; D011088:DNA Ligases; D000072481:DNA Ligase ATP; C000618816:DNA ligase III alpha protein, Xenopus; C000618817:LIG3 protein, human; C000618818:Lig3 protein, mouse