Reference SummaryWoo Y, Oncogene 2007 Sep 6;26(41):6010-20

Title

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

Authors

Woo Y; Wright SM; Maas SA; Alley TL; Caddle LB; Kamdar S; Affourtit J; Foreman O; Akeson EC; Shaffer D; Bronson RT; Morse HC 3rd; Roopenian D; Mills KD

Journal

Oncogene

Volume

26

Issue

41

Year

2007

Pages

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.

Links

J:130286 – Mouse Genome Informatics
17384673 – National Library of Medicine/PubMed

Models

Strain Model Name Treatment Agent(s) Organ Affected Frequency Model Details
B6;129-Dclre1ctm1Fwa Trp53tm1Brd/+ Bone osteosarcoma Bone

7.0

B6;129-Dclre1ctm1Fwa Trp53tm1Brd/+ CNS - Brain glioma - malignant CNS - Brain

2.8

B6;129-Dclre1ctm1Fwa Trp53tm1Brd/+ Leukocyte - Lymphocyte - Pro-B-lymphocyte lymphoma Leukocyte - Lymphocyte - Pro-B-lymphocyte

13

B6;129-Dclre1ctm1Fwa Trp53tm1Brd Leukocyte - Lymphocyte - Pro-B-lymphocyte lymphoma Leukocyte - Lymphocyte - Pro-B-lymphocyte

100

B6;129-Dclre1ctm1Fwa Trp53tm1Brd/+ Mesodermal cell/mesoblast sarcoma Mesodermal cell/mesoblast

9.9

B6;129-Dclre1ctm1Fwa Trp53tm1Brd/+ Mesodermal cell/mesoblast sarcoma - anaplastic Mesodermal cell/mesoblast

2.8

B6;129-Dclre1ctm1Fwa Trp53tm1Brd/+ (Unspecified organ) tumor (Unspecified organ)

18 - 34

B6;129-Trp53tm1Brd/+ (Unspecified organ) tumor (Unspecified organ)

0

B6;129-Dclre1ctm1Fwa (Unspecified organ) tumor (Unspecified organ)

0

B6;129-Dclre1ctm1Fwa Trp53tm1Brd/+ (Unspecified organ) tumor - benign (Unspecified organ)

8.5