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. (March 2006) Role of genomic instability and p53 in AID-induced c-myc-Igh translocations. Nature, 440 (7080). pp. 105-109. ISSN 00280836
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. © 2006 Nature Publishing Group.
| Item Type: | Paper |
|---|---|
| Subjects: | diseases & disorders > cancer > cancer types > B cell lymphoma diseases & disorders > cancer |
| CSHL Authors: | |
| Communities: | CSHL labs > Lowe lab |
| Depositing User: | CSHL Librarian |
| Date: | March 2006 |
| Date Deposited: | 09 Dec 2011 19:58 |
| Last Modified: | 11 Apr 2018 18:57 |
| PMCID: | PMC4601098 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/22881 |
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