Impaired nonhomologous end-joining provokes soft tissue sarcomas harboring chromosomal translocations,
N E Sharpless1, D O Ferguson, R C O'Hagan
1Department of Adult Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
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.
Insights
Reduced DNA ligase IV (Lig4) activity in mice accelerates non-lymphoid tumor formation. Haploinsufficiency of Lig4 leads to genomic instability and soft-tissue sarcomas, highlighting its role in cancer suppression.
Area of Science:
- Genetics
- Cancer Biology
- Genomic Instability
Background:
- Nonhomologous end-joining (NHEJ) is crucial for DNA repair.
- NHEJ deficiency accelerates lymphoma but its role in other cancers is unclear.
Purpose of the Study:
- To investigate the role of DNA ligase IV (Lig4) haploinsufficiency in non-lymphoid tumorigenesis.
- To determine if reduced NHEJ activity drives cancer in cells without V(D)J recombination.
Main Methods:
- Utilized ink4a/arf(-/-) tumor-prone mice.
- Examined the effect of lig4 heterozygosity on tumor development.
- Analyzed genomic alterations in tumors, including amplifications, deletions, and translocations.
Main Results:
- Lig4 heterozygosity promoted soft-tissue sarcoma development in mice.
- Tumors exhibited clonal genomic aberrations like amplifications, deletions, and translocations.
- Frequent mdm2 amplification, an oncogene in human sarcoma, was observed.
Conclusions:
- Loss of a single lig4 allele sufficiently reduces NHEJ activity.
- Reduced NHEJ activity leads to chromosomal aberrations that drive non-lymphoid tumorigenesis.
- Lig4 plays a significant role in suppressing non-lymphoid cancers.
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