Abstract
Chromosomal translocations involving the immunoglobulin switch region are a hallmark feature of B-cell malignancies1. However, little is known about the molecular mechanism by which primary B cells acquire or guard against these lesions. Here we find that translocations between c-myc and the IgH locus (Igh) are induced in primary B cells within hours of expression of the catalytically active form of activation-induced cytidine deaminase (AID), an enzyme that deaminates cytosine to produce uracil in DNA2,3. Translocation also requires uracil DNA glycosylase (UNG), which removes uracil from DNA to create abasic sites that are then processed to double-strand breaks4,5. The pathway that mediates aberrant joining of c-myc and Igh differs from intrachromosomal repair during immunoglobulin class switch recombination in that it does not require histone H2AX6, p53 binding protein 1 (53BP1)7,8 or the non-homologous end-joining protein Ku809. In addition, translocations are inhibited by the tumour suppressors ATM, Nbs1, p19 (Arf) and p53, which is consistent with activation of DNA damage- and oncogenic stress-induced checkpoints during physiological class switching. Finally, we demonstrate that accumulation of AID-dependent, IgH-associated chromosomal lesions is not sufficient to enhance c-myc–Igh translocations. Our findings reveal a pathway for surveillance and protection against AID-dependent DNA damage, leading to chromosomal translocations.
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Acknowledgements
We thank T. Honjo for Aid-/- mice, M. Bosma for DNA-PKcs-/- mice, R. Jaenisch for Ung-/- mice, A. Singer and E. Besmer for suggestions, K. Velinzon for flow cytometry, and L. Stapelton for painting probes. A.N. was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research and a grant from the AT Childrens Project. S.W.L. was supported by grants from the National Cancer Institute. A.R.R. is a Ramon y Cajal investigator from Ministerio de Educacion y Ciencia, Spain. M.C.N. was supported by grants from the NIH and the Leukemia Society. M.C.N. is a Howard Hughes Institute Investigator. Author Contributions The last two authors (A.N. and M.C.N.) contributed equally to this work.
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Ramiro, A., Jankovic, M., Callen, E. et al. Role of genomic instability and p53 in AID-induced c-myc–Igh translocations. Nature 440, 105–109 (2006). https://doi.org/10.1038/nature04495
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DOI: https://doi.org/10.1038/nature04495
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