Aberrantly Resolved RAG-Mediated DNA Breaks in Atm-Deficient Lymphocytes Target Chromosomal Breakpoints in cis

• Published in: Proceedings of the National Academy of Sciences - PNAS 2009-10, Vol.106 (43), p.18339-18344
• Main Authors: Mahowald, Grace K., Baron, Jason M., Mahowald, Michael A., Kulkarni, Shashikant, Bredemeyer, Andrea L., Bassing, Craig H., Sleckman, Barry P.
• Format: Article
• Language: English
• Subjects: Animals; Antigen receptors; Antigens; Ataxia Telangiectasia Mutated Proteins; Biological Sciences; Cell cycle; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell Line; Cell lines; Chromosome Breakage; Chromosomes; Chromosomes, Mammalian - metabolism; Deoxyribonucleic acid; DNA; DNA Breaks, Double-Stranded; DNA-Binding Proteins - deficiency; DNA-Binding Proteins - genetics; DNA-Binding Proteins - immunology; DNA-Binding Proteins - metabolism; Gene loci; Genes; Genetic loci; Homeodomain Proteins - genetics; Homeodomain Proteins - immunology; Homeodomain Proteins - metabolism; Lesions; Lymphocytes; Lymphocytes - immunology; Lymphocytes - metabolism; Mice; Mice, Knockout; Polymerase chain reaction; Protein-Serine-Threonine Kinases - deficiency; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Receptors, Antigen - immunology; Rodents; T lymphocytes; Translocation, Genetic; Tumor Suppressor Proteins - deficiency; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0902545106

Canonical chromosomal translocations juxtaposing antigen receptor genes and oncogenes are a hallmark of many lymphoid malignancies. These translocations frequently form through the joining of DNA ends from double-strand breaks (DSBs) generated by the recombinase activating gene (RAG)-1 and -2 proteins at lymphocyte antigen receptor loci and breakpoint targets near oncogenes. Our understanding of chromosomal breakpoint target selection comes primarily from the analyses of these lesions, which are selected based on their transforming properties. RAG DSBs are rarely resolved aberrantly in wild-type developing lymphocytes. However, in ataxia telangiectasia mutated (ATM)-deficient lymphocytes, RAG breaks are frequently joined aberrantly, forming chromosomal lesions such as translocations that predispose (ATM)-deficient mice and humans to the development of lymphoid malignancies. Here, an approach that minimizes selection biases is used to isolate a large cohort of breakpoint targets of aberrantly resolved RAG DSBs in Atm-deficient lymphocytes. Analyses of this cohort revealed that frequently, the breakpoint targets for aberrantly resolved RAG breaks are other DSBs. Moreover, these nonselected lesions exhibit a bias for using breakpoints in cis, forming small chromosomal deletions, rather than breakpoints in trans, forming chromosomal translocations.