UNG protects B cells from AID-induced telomere loss

Elena M. Cortizas, Astrid Zahn, Shiva Safavi, Joseph A. Reed, Francisco Vega, Javier M. Di Noia, Ramiro E. Verdun

Research output: Contribution to journalArticlepeer-review

17 Scopus citations


Activation-induced deaminase (AID) initiates antibody gene diversification by creating G:U mismatches in the immunoglobulin loci. However, AID also deaminates nonimmunoglobulin genes, and failure to faithfully repair these off-target lesions can cause B cell lymphoma. In this study, we identify a mechanism by which processing of G:U produced by AID at the telomeres can eliminate B cells at risk of genomic instability. We show that telomeres are off-target substrates of AID and that B cell proliferation depends on protective repair by uracil-DNA glycosylase (UNG). In contrast, in the absence of UNG activity, deleterious processing by mismatch repair leads to telomere loss and defective cell proliferation. Indeed, we show that UNG deficiency reduces B cell clonal expansion in the germinal center in mice and blocks the proliferation of tumor B cells expressing AID. We propose that AID-induced damage at telomeres acts as a fail-safe mechanism to limit the tumor promoting activity of AID when it overwhelms uracil excision repair.

Original languageEnglish (US)
Pages (from-to)2459-2472
Number of pages14
JournalJournal of Experimental Medicine
Issue number11
StatePublished - Oct 17 2016

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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