AID Is Required for the Chromosomal Breaks in c-myc that Lead to c-myc/IgH Translocations

Chromosomal translocation requires formation of paired double-strand DNA breaks (DSBs) on heterologous chromosomes. One of the most well characterized oncogenic translocations juxtaposes c-myc and the immunoglobulin heavy-chain locus ( IgH) and is found in Burkitt's lymphomas in humans and plas...

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Bibliographic Details
Published in:Cell 2008-12, Vol.135 (6), p.1028-1038
Main Authors: Robbiani, Davide F., Bothmer, Anne, Callen, Elsa, Reina-San-Martin, Bernardo, Dorsett, Yair, Difilippantonio, Simone, Bolland, Daniel J., Chen, Hua Tang, Corcoran, Anne E., Nussenzweig, André, Nussenzweig, Michel C.
Format: Article
Language:English
Subjects:
Animals
B-Lymphocytes - metabolism
Burkitt Lymphoma - genetics
Burkitt Lymphoma - metabolism
CELLBIO
Cellular Biology
Cytidine Deaminase - metabolism
DNA Breaks, Double-Stranded
Embryonic Stem Cells
Genes, Immunoglobulin Heavy Chain
Genes, myc
Humans
HUMDISEASE
Integrases - metabolism
Life Sciences
Mice
Mice, Inbred C57BL
MOLIMMUNO
Plasmacytoma - genetics
Plasmacytoma - metabolism
Translocation, Genetic
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Summary:Chromosomal translocation requires formation of paired double-strand DNA breaks (DSBs) on heterologous chromosomes. One of the most well characterized oncogenic translocations juxtaposes c-myc and the immunoglobulin heavy-chain locus ( IgH) and is found in Burkitt's lymphomas in humans and plasmacytomas in mice. DNA breaks in IgH leading to c-myc/IgH translocations are created by activation-induced cytidine deaminase (AID) during antibody class switch recombination or somatic hypermutation. However, the source of DNA breaks at c-myc is not known. Here, we provide evidence for the c-myc promoter region being required in targeting AID-mediated DNA damage to produce DSBs in c-myc that lead to c-myc/IgH translocations in primary B lymphocytes. Thus, in addition to producing somatic mutations and DNA breaks in antibody genes, AID is also responsible for the DNA lesions in oncogenes that are required for their translocation.
ISSN:0092-8674
1097-4172
DOI:10.1016/j.cell.2008.09.062