Reference SummaryDifilippantonio MJ, J Exp Med 2002 Aug 19;196(4):469-80

Title

Evidence for replicative repair of DNA double-strand breaks leading to oncogenic translocation and gene amplification.

Authors

Difilippantonio MJ; Petersen S; Chen HT; Johnson R; Jasin M; Kanaar R; Ried T; Nussenzweig A

Journal

J Exp Med

Volume

196

Issue

4

Year

2002

Pages

469-80

Abstract

Nonreciprocal translocations and gene amplifications are commonly found in human tumors. Although little is known about the mechanisms leading to such aberrations, tissue culture models predict that they can arise from DNA breakage, followed by cycles of chromatid fusion, asymmetric mitotic breakage, and replication. Mice deficient in both a nonhomologous end joining (NHEJ) DNA repair protein and the p53 tumor suppressor develop lymphomas at an early age harboring amplification of an IgH/c-myc fusion. Here we report that these chromosomal rearrangements are initiated by a recombination activating gene (RAG)-induced DNA cleavage. Subsequent DNA repair events juxtaposing IgH and c-myc are mediated by a break-induced replication pathway. Cycles of breakage-fusion-bridge result in amplification of IgH/c-myc while chromosome stabilization occurs through telomere capture. Thus, mice deficient in NHEJ provide excellent models to study the etiology of unbalanced translocations and amplification events during tumorigenesis.

Links

J:78496 – Mouse Genome Informatics
12186839 – National Library of Medicine/PubMed

Models

Strain Model Name Treatment Agent(s) Organ Affected Frequency Model Details
[not specified]-Xrcc5tm1Nus Leukocyte - Lymphocyte - Immature T-lymphocyte lymphoma Thymus

observed

[not specified]-Atmtm1Awb/+ Xrcc5tm1Nus Leukocyte - Lymphocyte - Immature T-lymphocyte lymphoma Thymus

observed

[not specified]-Trp53tm1Brd Xrcc5tm1Nus Leukocyte - Lymphocyte - Pro-B-lymphocyte lymphoma Leukocyte - Lymphocyte - Pro-B-lymphocyte

observed

[not specified]-Trp53tm1Brd Xrcc6tm1Fwa Leukocyte - Lymphocyte - Pro-B-lymphocyte lymphoma Leukocyte - Lymphocyte - Pro-B-lymphocyte

very high

[not specified]-Rad54ltm1Jhjh Trp53tm1Brd Xrcc5tm1Nus Leukocyte - Lymphocyte - Pro-B-lymphocyte lymphoma Leukocyte - Lymphocyte - Pro-B-lymphocyte

observed

[not specified]-Rag2tm1Fwa Trp53tm1Brd Xrcc5tm1Nus Leukocyte - Lymphocyte - Pro-B-lymphocyte lymphoma Leukocyte - Lymphocyte - Pro-B-lymphocyte

0

[not specified]-Rad54ltm1Jhjh Trp53tm1Brd Xrcc5tm1Nus Leukocyte lymphoma Thymus

observed

[not specified]-Rad54ltm1Jhjh Trp53tm1Brd/+ Xrcc5tm1Nus Leukocyte lymphoma Thymus

20

[not specified]-Rag2tm1Fwa Trp53tm1Brd Xrcc5tm1Nus Leukocyte lymphoma Thymus

observed

[not specified]-Rag2tm1Fwa Tg(AND)# Trp53tm1Brd Xrcc5tm1Nus Leukocyte lymphoma Thymus

observed

[not specified]-Rag2tm1Fwa Tg(AND)# Trp53tm1Brd Xrcc5tm1Nus/+ Leukocyte lymphoma Thymus

observed