The nonhomologous end joining factor Artemis suppresses multi-tissue tumor formation and prevents loss of heterozygosity

Yong Woo, S. M. Wright, S. A. Maas, T. L. Alley, L. B. Caddle, S. Kamdar, J. Affourtit, O. Foreman, E. C. Akeson, D. Shaffer, R. T. Bronson, H. C. Morse, D. Roopenian, K. D. Mills*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)6010-6020
Number of pages11
JournalOncogene
Volume26
Issue number41
DOIs
StatePublished - Sep 6 2007

Keywords

  • Artemis
  • Loss of heterozygosity
  • Nonhomologous end joining
  • RS-SCID
  • p53

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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