Role of genomic instability and p53 in AID-induced c-myc-Igh translocations

Almudena R. Ramiro, Mila Jankovic, Elsa Callen, Simone Difilippantonio, Hua Tang Chen, Kevin M. McBride, Thomas R. Eisenreich, Junjie Chen, Ross A. Dickins, Scott W. Lowe, Andre Nussenzweig, Michel C. Nussenzweig

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267 Scopus citations

Abstract

Chromosomal translocations involving the immunoglobulin switch region are a hallmark feature of B-cell malignancies. 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 DNA. Translocation also requires uracil DNA glycosylase (UNG), which removes uracil from DNA to create abasic sites that are then processed to double-strand breaks. 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 H2AX, p53 binding protein 1 (53BP1) or the non-homologous end-joining protein Ku80. 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.

Original languageEnglish (US)
Pages (from-to)105-109
Number of pages5
JournalNature
Volume440
Issue number7080
DOIs
StatePublished - Mar 2 2006

ASJC Scopus subject areas

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    Ramiro, A. R., Jankovic, M., Callen, E., Difilippantonio, S., Chen, H. T., McBride, K. M., Eisenreich, T. R., Chen, J., Dickins, R. A., Lowe, S. W., Nussenzweig, A., & Nussenzweig, M. C. (2006). Role of genomic instability and p53 in AID-induced c-myc-Igh translocations. Nature, 440(7080), 105-109. https://doi.org/10.1038/nature04495