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Article
A DNA break- and phosphorylation-dependent positive feedback loop promotes immunoglobulin class-switch recombination
University of Massachusetts Medical School Faculty Publications
  • Bao Q. Vuong, Gerstner Sloan-Kettering Graduate School
  • Kayleigh Herrick-Reynolds, Gerstner Sloan-Kettering Graduate School
  • Bharat Vaidyanathan, Gerstner Sloan-Kettering Graduate School
  • Joseph N. Pucella, Gerstner Sloan-Kettering Graduate School
  • Anna J. Ucher, Unviersity of Massachusetts Medical School
  • Nina M. Donghia, The Jackson Laboratory
  • Xiwen Gu, Yale University School of Medicine
  • Laura Nicolas, Gerstner Sloan-Kettering Graduate School
  • Urszula Nowak, Gerstner Sloan-Kettering Graduate School
  • Numa Rahman, Gerstner Sloan-Kettering Graduate School
  • Matthew P. Strout, Yale University School of Medicine
  • Kevin D. Mills, The Jackson Laboratory
  • Janet Stavnezer, University of Massachusetts Medical School
  • Jayanta Chaudhuri, Gerstner Sloan-Kettering Graduate School
UMMS Affiliation
Department of Microbiology and Physiological Systems
Date
11-1-2013
Document Type
Article
Medical Subject Headings
Animals; Ataxia Telangiectasia Mutated Proteins; B-Lymphocytes; Cytidine Deaminase; DNA Breaks, Double-Stranded; DNA-(Apurinic or Apyrimidinic Site) Lyase; *Feedback, Physiological; Gene Expression Regulation; *Immunoglobulin Class Switching; Immunoglobulin Heavy Chains; Mice; Phosphorylation; Protein Binding; Serine; Signal Transduction
Abstract
The ability of activation-induced cytidine deaminase (AID) to efficiently mediate class-switch recombination (CSR) is dependent on its phosphorylation at Ser38; however, the trigger that induces AID phosphorylation and the mechanism by which phosphorylated AID drives CSR have not been elucidated. Here we found that phosphorylation of AID at Ser38 was induced by DNA breaks. Conversely, in the absence of AID phosphorylation, DNA breaks were not efficiently generated at switch (S) regions in the immunoglobulin heavy-chain locus (Igh), consistent with a failure of AID to interact with the endonuclease APE1. Additionally, deficiency in the DNA-damage sensor ATM impaired the phosphorylation of AID at Ser38 and the interaction of AID with APE1. Our results identify a positive feedback loop for the amplification of DNA breaks at S regions through the phosphorylation- and ATM-dependent interaction of AID with APE1.
Rights and Permissions
Citation: Nat Immunol. 2013 Nov;14(11):1183-9. doi: 10.1038/ni.2732. Epub 2013 Oct 6. Link to article on publisher's site
Related Resources
Link to Article in PubMed
PubMed ID
24097111
Citation Information
Bao Q. Vuong, Kayleigh Herrick-Reynolds, Bharat Vaidyanathan, Joseph N. Pucella, et al.. "A DNA break- and phosphorylation-dependent positive feedback loop promotes immunoglobulin class-switch recombination" Vol. 14 Iss. 11 (2013) ISSN: 1529-2908 (Linking)
Available at: http://works.bepress.com/stavnezerj/109/