The nonhomologous end joining factor Artemis suppresses multi-tissue tumor formation and prevents loss of heterozygosity.
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.
Woo
Y
Y
The Jackson Laboratory, Bar Harbor, ME 04609, USA.
Wright
S M
SM
Maas
S A
SA
Alley
T L
TL
Caddle
L B
LB
Kamdar
S
S
Affourtit
J
J
Foreman
O
O
Akeson
E C
EC
Shaffer
D
D
Bronson
R T
RT
Morse
H C
HC
Roopenian
D
D
Mills
K D
KD
D000818:Animals; D004260:DNA Repair; D004720:Endonucleases; D016158:Genes, p53; D006801:Humans; D019656:Loss of Heterozygosity; D008223:Lymphoma / Q000235:genetics / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology*; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics*; D012513:Sarcoma, Experimental / Q000235:genetics / Q000473:pathology; D016511:Severe Combined Immunodeficiency / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency
D009687:Nuclear Proteins; D016159:Tumor Suppressor Protein p53; D004720:Endonucleases; C473337:Dclre1c protein, mouse