Mechanism of DNA resection during intrachromosomal recombination and immunoglobulin class switching

Anne Bothmer, Philipp C. Rommel, Anna Gazumyan, Federica Polato, Colleen R. Reczek, Matthias F. Muellenbeck, Sonja Schaetzlein, Winfried Edelmann, Phang Lang Chen, Robert M. Brosh, Rafael Casellas, Thomas Ludwig, Richard Baer, André Nussenzweig, Michel C. Nussenzweig, Davide F. Robbiani

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33 Scopus citations

Abstract

DNA double-strand breaks (DSBs) are byproducts of normal cellular metabolism and obligate intermediates in antigen receptor diversification reactions. These lesions are potentially dangerous because they can lead to deletion of genetic material or chromosome translocation. The chromatin-binding protein 53BP1 and the histone variant H2AX are required for efficient class switch (CSR) and V(D)J recombination in part because they protect DNA ends from resection and thereby favor nonhomologous end joining (NHEJ). Here, we examine the mechanism of DNA end resection in primary B cells. We find that resection depends on both CtBP-interacting protein (CtIP, Rbbp8) and exonuclease 1 (Exo1). Inhibition of CtIP partially rescues the CSR defect in 53BP1- and H2AX-deficient lymphocytes, as does interference with the RecQ helicases Bloom (Blm) and Werner (Wrn). We conclude that CtIP, Exo1, and RecQ helicases contribute to the metabolism of DNA ends during DSB repair in B lymphocytes and that minimizing resection favors efficient CSR.

Original languageEnglish (US)
Pages (from-to)115-123
Number of pages9
JournalJournal of Experimental Medicine
Volume210
Issue number1
DOIs
StatePublished - Jan 1 2013

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ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Bothmer, A., Rommel, P. C., Gazumyan, A., Polato, F., Reczek, C. R., Muellenbeck, M. F., Schaetzlein, S., Edelmann, W., Chen, P. L., Brosh, R. M., Casellas, R., Ludwig, T., Baer, R., Nussenzweig, A., Nussenzweig, M. C., & Robbiani, D. F. (2013). Mechanism of DNA resection during intrachromosomal recombination and immunoglobulin class switching. Journal of Experimental Medicine, 210(1), 115-123. https://doi.org/10.1084/jem.20121975