Nonhomologous end joining (NHEJ) is a critical DNA repair pathway, with proposed tumor suppression functions in many tissues. Mutations in the NHEJ factor ARTEMIS cause radiation-sensitive severe combined immunodeficiency in humans and may increase susceptibility to lymphoma in some settings. We now report that deficiency for Artemis (encoded by Dclre1c/Art in mouse) accelerates tumorigenesis in several tissues in a Trp53 heterozygous setting, revealing tumor suppression roles for NHEJ in lymphoid and non-lymphoid cells. We also show that B-lineage lymphomas in these mice undergo loss of Trp53 heterozygosity by allele replacement, but arise by mechanisms distinct from those in Art Trp53 double null mice. These findings demonstrate a general tumor suppression function for NHEJ, and reveal that interplay between NHEJ and Trp53 loss of heterozygosity influences the sequence of multi-hit oncogenesis. We present a model where p53 status at the time of tumor initiation is a key determinant of subsequent oncogenic mechanisms. Because Art deficient mice represent a model for radiation-sensitive severe combined immunodeficiency, our findings suggest that these patients may be at risk for both lymphoid and non-lymphoid cancers.
|Original language||English (US)|
|Number of pages||11|
|State||Published - Sep 6 2007|
Bibliographical noteFunding Information:
We thank the members of the Mills lab, as well as Frederick Alt, Shaoguang Li, Mitch McVey and Lindsay Shopland for helpful comments and discussions, Kathy Snow for technical assistance, and Jin Szatkiewicz for statistical analysis. This work was supported by NIH grant R01 CA115665. SAM was supported by NIH Training Grant T32 HD07065-27. YHW was supported by NSF IGERT Training Grant 0221625 (University of Maine; Knowles, PI). D Roopenian and D Shaffer are founders of Bar Harbor Biotechnology.
- Loss of heterozygosity
- Nonhomologous end joining
ASJC Scopus subject areas
- Molecular Biology
- Cancer Research