Impaired nonhomologous end-joining provokes soft tissue sarcomas harboring chromosomal translocations, amplifications, and deletions

Mol Cell. 2001 Dec;8(6):1187-96. doi: 10.1016/s1097-2765(01)00425-7.


Although nonhomologous end-joining (NHEJ) deficiency has been shown to accelerate lymphoma formation in mice, its role in suppressing tumors in cells that do not undergo V(D)J recombination is unclear. Utilizing a tumor-prone mouse strain (ink4a/arf(-/-)), we examined the impact of haploinsufficiency of a NHEJ component, DNA ligase IV (Lig4), on murine tumorigenesis. We demonstrate that lig4 heterozygosity promotes the development of soft-tissue sarcomas that possess clonal amplifications, deletions, and translocations. That these genomic alterations are relevant in tumorigenesis is supported by the finding of frequent mdm2 amplification, a known oncogene in human sarcoma. Together, these findings support the view that loss of a single lig4 allele results in NHEJ activity being sufficiently reduced to engender chromosomal aberrations that drive non-lymphoid tumorigenesis.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cell Transformation, Neoplastic
  • Cells, Cultured
  • Chromosome Deletion*
  • Cyclin-Dependent Kinase Inhibitor p16 / deficiency
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics
  • DNA Damage / genetics
  • DNA Ligase ATP
  • DNA Ligases / genetics*
  • DNA Ligases / physiology
  • Fibroblasts
  • Gene Amplification / genetics*
  • Gene Deletion
  • Heterozygote
  • Loss of Heterozygosity / genetics
  • Mice
  • Mice, Knockout
  • Mice, SCID
  • Mutagenesis / genetics
  • Sarcoma / enzymology
  • Sarcoma / genetics*
  • Sarcoma / pathology
  • Translocation, Genetic / genetics*
  • Tumor Suppressor Protein p14ARF / deficiency
  • Tumor Suppressor Protein p14ARF / genetics


  • Cdkn2a protein, mouse
  • Cyclin-Dependent Kinase Inhibitor p16
  • LIG4 protein, human
  • Tumor Suppressor Protein p14ARF
  • DNA Ligases
  • DNA Ligase ATP