Targeted disruption of the gene encoding DNA ligase IV leads to lethality in embryonic mice

Curr Biol. 1998 Dec 17-31;8(25):1395-8. doi: 10.1016/s0960-9822(98)00021-9.

Abstract

DNA ligase IV is the most recently identified member of a family of enzymes joining DNA strand breaks in mammalian cell nuclei [1] [2]. The enzyme occurs in a complex with the XRCC4 gene product [3], an interaction mediated via its unique carboxyl terminus [4] [5]. Cells lacking XRCC4 are hypersensitive to ionising radiation and defective in V(D)J recombination [3] [6], implicating DNA ligase IV in the pathway of nonhomologous end-joining (NHEJ) of DNA double-strand breaks mediated by XRCC4, the Ku70/80 heterodimer and the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) in mammalian cells (reviewed in [7]). The phenotype of a null mutant of the Saccharomyces cerevisiae DNA ligase IV homologue indicates that the enzyme is non-essential and functions in yeast NHEJ [8] [9] [10]. Unlike other mammalian DNA ligases for which cDNAs have been characterised, DNA ligase IV is encoded by an intronless gene (LIG4). Here, we show that targeted disruption of LIG4 in the mouse leads to lethality associated with extensive apoptotic cell death in the embryonic central nervous system. Thus, unlike Ku70/80 and DNA-PKcs [11] [12] [13] [14], DNA ligase IV has an essential function in early mammalian development.

MeSH terms

  • Animals
  • Apoptosis
  • Central Nervous System / embryology
  • Central Nervous System / enzymology*
  • Central Nervous System / pathology
  • DNA Ligase ATP
  • DNA Ligases / genetics
  • DNA Ligases / physiology*
  • Embryo, Mammalian / enzymology*
  • Embryo, Mammalian / pathology
  • Gene Targeting
  • Genes, Lethal
  • Genotype
  • In Situ Nick-End Labeling
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout

Substances

  • DNL4 protein, S cerevisiae
  • DNA Ligases
  • DNA Ligase ATP