| AID- and Ung-dependent generation of staggered double-strand DNA breaks in immunoglobulin class switch DNA recombination: a post-cleavage role for AID. | |
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MedLine Citation:
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PMID: 18760480 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Class switch DNA recombination (CSR) substitutes an immunoglobulin (Ig) constant heavy chain (C(H)) region with a different C(H) region, thereby endowing an antibody with different biological effector functions. CSR requires activation-induced cytidine deaminase (AID) and occurrence of double-strand DNA breaks (DSBs) in S regions of upstream and downstream C(H) region genes. DSBs are critical for CSR and would be generated through deamination of dC by AID, subsequent dU deglycosylation by uracil DNA glycosylase (Ung) and nicking by apurinic/apyrimidic endonuclease (APE) of nearby abasic sites on opposite DNA strands. We show here that in human and mouse B cells, S region DSBs can be generated in an AID- and Ung-independent fashion. These DSBs are blunt and 5'-phosphorylated. In B cells undergoing CSR, blunt and 5'-phosphorylated DSBs are processed in an AID- and Ung-dependent fashion to yield staggered DNA ends. Blunt and 5'-phosphorylated DSBs can be readily detected in human and mouse AID- or Ung-deficient B cells. These B cells are CSR defective, but show evidence of intra-S region recombination. Forced expression of AID in AID-negative B cells converts blunt S region DSBs to staggered DSBs. Conversely, forced expression of dominant negative AID or inhibition of Ung by Ung inhibitor (Ugi) in switching B cells abrogates the emergence of staggered DSBs and concomitant CSR. Thus, AID and Ung generate staggered DSBs not only by cleaving intact double-strand DNA, but also by processing blunt DSB ends, whose generation is AID- and Ung-independent, thereby outlining a post-cleavage role for AID in CSR. |
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Authors:
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Hong Zan; Paolo Casali |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2008-08-28 |
Journal Detail:
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Title: Molecular immunology Volume: 46 ISSN: 0161-5890 ISO Abbreviation: Mol. Immunol. Publication Date: 2008 Nov |
Date Detail:
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Created Date: 2008-10-17 Completed Date: 2009-04-08 Revised Date: 2010-12-03 |
Medline Journal Info:
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Nlm Unique ID: 7905289 Medline TA: Mol Immunol Country: England |
Other Details:
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Languages: eng Pagination: 45-61 Citation Subset: IM |
Affiliation:
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Center for Immunology, School of Medicine and School of Biological Sciences, University of California, 3028 Hewitt Hall, Irvine, CA 92697-4120, United States. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals B-Lymphocytes / enzymology, immunology Base Sequence Cytidine Deaminase / deficiency, metabolism* DNA / genetics, metabolism* DNA Breaks, Double-Stranded* DNA-Binding Proteins / metabolism Humans Immunoglobulin Class Switching* Mice Models, Immunological Molecular Sequence Data Mutation / genetics Phosphorylation Recombination, Genetic / genetics* Uracil-DNA Glycosidase / deficiency, metabolism* |
| Grant Support | |
ID/Acronym/Agency:
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AI 45011/AI/NIAID NIH HHS; AI 60573/AI/NIAID NIH HHS; AR 40908/AR/NIAMS NIH HHS; R01 AI045011-10/AI/NIAID NIH HHS; R01 AI079705-01A2/AI/NIAID NIH HHS; R01 AI079705-02/AI/NIAID NIH HHS; T32 AI060573-01A1/AI/NIAID NIH HHS; T32 AI060573-07/AI/NIAID NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/DNA-Binding Proteins; 9007-49-2/DNA; EC 3.2.2.-/Uracil-DNA Glycosidase; EC 3.5.4.-/AICDA (activation-induced cytidine deaminase); EC 3.5.4.5/Cytidine Deaminase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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