| AID produces DNA double-strand breaks in non-Ig genes and mature B cell lymphomas with reciprocal chromosome translocations. | |
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MedLine Citation:
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PMID: 19941823 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Cancer-initiating translocations such as those associated with lymphomas require the formation of paired DNA double-strand breaks (DSBs). Activation-induced cytidine deaminase (AID) produces widespread somatic mutation in mature B cells; however, the extent of "off-target" DSB formation and its role in translocation-associated malignancy is unknown. Here, we show that deregulated expression of AID causes widespread genome instability, which alone is insufficient to induce B cell lymphoma; transformation requires concomitant loss of the tumor suppressor p53. Mature B cell lymphomas arising as a result of deregulated AID expression are phenotypically diverse and harbor clonal reciprocal translocations involving a group of Immunoglobulin (Ig) and non-Ig genes that are direct targets of AID. This group includes miR-142, a previously unknown micro-RNA target that is translocated in human B cell malignancy. We conclude that AID produces DSBs throughout the genome, which can lead to lymphoma-associated chromosome translocations in mature B cells. |
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Authors:
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Davide F Robbiani; Samuel Bunting; Niklas Feldhahn; Anne Bothmer; Jordi Camps; Stephanie Deroubaix; Kevin M McBride; Isaac A Klein; Gary Stone; Thomas R Eisenreich; Thomas Ried; André Nussenzweig; Michel C Nussenzweig |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, N.I.H., Intramural; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Molecular cell Volume: 36 ISSN: 1097-4164 ISO Abbreviation: Mol. Cell Publication Date: 2009 Nov |
Date Detail:
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Created Date: 2009-11-27 Completed Date: 2009-12-16 Revised Date: 2011-05-30 |
Medline Journal Info:
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Nlm Unique ID: 9802571 Medline TA: Mol Cell Country: United States |
Other Details:
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Languages: eng Pagination: 631-41 Citation Subset: IM |
Affiliation:
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The Rockefeller University, New York, NY 10065, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals B-Lymphocytes / cytology, enzymology Cell Differentiation / genetics Cells, Cultured Chromosomal Instability / genetics Chromosomes, Mammalian / genetics* Cytidine Deaminase / metabolism* DNA Breaks, Double-Stranded* DNA Damage Genes, Immunoglobulin / genetics* Humans Immunoglobulin Class Switching / genetics Karyotyping Lymphoma, B-Cell / enzymology*, genetics*, pathology Mice Mice, Transgenic MicroRNAs / metabolism Phenotype Proto-Oncogene Proteins c-myc / genetics Somatic Hypermutation, Immunoglobulin / genetics Translocation, Genetic* Tumor Suppressor Protein p53 / deficiency |
| Grant Support | |
ID/Acronym/Agency:
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AI037526/AI/NIAID NIH HHS; GM07739/GM/NIGMS NIH HHS; R01 AI037526-16/AI/NIAID NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/MicroRNAs; 0/Mirn142 microRNA, mouse; 0/Proto-Oncogene Proteins c-myc; 0/Tumor Suppressor Protein p53; EC 3.5.4.-/AICDA (activation-induced cytidine deaminase); EC 3.5.4.5/Cytidine Deaminase |
| Comments/Corrections | |
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