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PMID: 19966290 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't

Role of the translocation partner in protection against AID-dependent chromosomal translocations.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 107 ·No. 1 ·2010-01-05 ·Pages 187-92

Jankovic M, Robbiani DF, Dorsett Y, Eisenreich T, Xu Y, Tarakhovsky A, Nussenzweig A, Nussenzweig MC

Abstract

Chromosome translocations between Ig (Ig) and non-Ig genes are frequently associated with B-cell lymphomas in humans and mice. The best characterized of these is c-myc/IgH translocation, which is associated with Burkitt's lymphoma. These translocations are caused by activation-induced cytidine deaminase (AID), which produces double-strand DNA breaks in both genes. c-myc/IgH translocations are rare events, in part because ATM, p53, and p19 actively suppress them. To further define the mechanism of protection against the accumulation of cells that bear c-myc/IgH translocation, we assayed B cells from mice that carry mutations in cell-cycle and apoptosis regulator proteins that act downstream of p53. We find that PUMA, Bim, and PKCdelta are required for protection against c-myc/IgH translocation, whereas Bcl-XL and BAFF enhance c-myc/IgH translocation. Whether these effects are general or specific to c-myc/IgH translocation and whether AID produces dsDNA breaks in genes other than c-myc and Ig is not known. To examine these questions, we developed an assay for translocation between IgH and Igbeta, both of which are somatically mutated by AID. Igbeta/IgH, like c-myc/IgH translocations, are AID-dependent, and AID is responsible for lesions on IgH and the non-IgH translocation partners. However, ATM, p53, and p19 do not protect against Igbeta/IgH translocations. Instead, B cells are protected against Igbeta/IgH translocations by a BAFF- and PKCdelta-dependent pathway. We conclude that AID-induced double-strand breaks in non-Ig genes other than c-myc lead to their translocation, and that at least two nonoverlapping pathways protect against translocations in primary B cells.

MeSH Terms
Animals Apoptosis Regulatory Proteins/genetics,metabolism Ataxia Telangiectasia Mutated Proteins B-Lymphocytes/immunology Bcl-2-Like Protein 11 Cell Cycle Proteins/genetics,metabolism Cell Transformation, Neoplastic Cells, Cultured Cyclin-Dependent Kinase Inhibitor p19/genetics,metabolism Cytidine Deaminase/genetics,metabolism DNA-Binding Proteins/genetics,metabolism Genes, Immunoglobulin Humans Membrane Proteins/genetics,metabolism Mice Mice, Knockout Protein Kinase C-delta/genetics,immunology Protein Serine-Threonine Kinases/genetics,metabolism Proto-Oncogene Proteins/genetics,metabolism Proto-Oncogene Proteins c-myc/genetics,metabolism Somatic Hypermutation, Immunoglobulin Translocation, Genetic Tumor Suppressor Protein p53/genetics,metabolism Tumor Suppressor Proteins/genetics,metabolism
Chemicals
Apoptosis Regulatory Proteins BCL2L11 protein, human Bcl-2-Like Protein 11 Bcl2l11 protein, mouse Cell Cycle Proteins Cyclin-Dependent Kinase Inhibitor p19 DNA-Binding Proteins Membrane Proteins Myc protein, mouse PUMA protein, mouse Proto-Oncogene Proteins Proto-Oncogene Proteins c-myc Tumor Suppressor Protein p53 Tumor Suppressor Proteins ATM protein, human Ataxia Telangiectasia Mutated Proteins Atm protein, mouse Protein Serine-Threonine Kinases Protein Kinase C-delta AICDA (activation-induced cytidine deaminase) Cytidine Deaminase
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Jankovic Mila
Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA.
Robbiani Davide F
Dorsett Yair
Eisenreich Thomas
Xu Yang
Tarakhovsky Alexander
Nussenzweig Andre
Nussenzweig Michel C
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
1091-6490
DOI
10.1073/pnas.0908946107
Published
2010-01-05
Epub
2009-00-04
Pages
187-92
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC2806756
Subset
IM
Grants
NIAID NIH HHS · R01 AI037526 · United States
Howard Hughes Medical Institute · United States
Intramural NIH HHS · United States
NIAID NIH HHS · AI037526 · United States
NIAID NIH HHS · R37 AI037526 · United States
External Links
PubMed source DOI: 10.1073/pnas.0908946107 PMC Full Text View journal details
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