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 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.
Robbiani
Davide F
DF
Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA.
Bothmer
Anne
A
Callen
Elsa
E
Reina-San-Martin
Bernardo
B
Dorsett
Yair
Y
Difilippantonio
Simone
S
Bolland
Daniel J
DJ
Chen
Hua Tang
HT
Corcoran
Anne E
AE
Nussenzweig
André
A
Nussenzweig
Michel C
MC
D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism; D002051:Burkitt Lymphoma / Q000235:genetics / Q000378:metabolism; D003564:Cytidine Deaminase / Q000378:metabolism*; D053903:DNA Breaks, Double-Stranded; D053595:Embryonic Stem Cells; D050438:Genes, Immunoglobulin Heavy Chain; D016259:Genes, myc; D006801:Humans; D019426:Integrases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010954:Plasmacytoma / Q000235:genetics / Q000378:metabolism; D014178:Translocation, Genetic; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
C045073:Cre recombinase; D019426:Integrases; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase