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

Norman E. Sharpless, David O. Ferguson, Rónán C. O’hagan, Diego H. Castrillon, Charles Lee, Paraskevi A. Farazi, Scott Alson, James Fleming, Cynthia C. Morton, Karen Frank, Lynda Chin, Frederick W. Alt, Ronald A. DePinho

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)1187-1196
Number of pages10
JournalMolecular Cell
Volume8
Issue number6
DOIs
Publication statusPublished - Jan 1 2001

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ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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