The nonhomologous end joining factor Artemis suppresses multi-tissue tumor formation and prevents loss of heterozygosity.
Document Type
Article
Publication Date
2007
Keywords
DNA-Repair, Genes-p53, Humans, Loss-of-Heterozygosity, Lymphoma, Mice-Knockout, Neoplasms, Nuclear-Proteins, Sarcoma-Experimental, Severe-Combined-Immunodeficiency, Tumor-Suppressor-Protein-p53
First Page
6010
Last Page
6020
JAX Source
Oncogene 2007 Sep; 26(41):6010-20.
Abstract
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.
Recommended Citation
Woo Y,
Wright SM,
Maas SA,
Alley TL,
Caddle LB,
Kamdar S,
Affourtit J,
Foreman O,
Akeson EC,
Shaffer D,
Bronson RT,
Morse HC,
Roopenian D,
Mills KD.
The nonhomologous end joining factor Artemis suppresses multi-tissue tumor formation and prevents loss of heterozygosity. Oncogene 2007 Sep; 26(41):6010-20.