@article{749ac3a2b11b4ff88cc28868008903d2,
title = "UNG protects B cells from AID-induced telomere loss",
abstract = "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.",
author = "Cortizas, {Elena M.} and Astrid Zahn and Shiva Safavi and Reed, {Joseph A.} and Francisco Vega and {Di Noia}, {Javier M.} and Verdun, {Ramiro E.}",
note = "Funding Information: This work was supported by grants from the National Institute of Allergy and Infectious Diseases (R56-AI106894-01A1), the Miami Center for AIDS Research (1P30AI073961 to R.E. Verdun), and the Canadian Institutes of Health Research (MOP130535 to J.M. Di Noia). J.M. Di Noia holds a Canada Research Chair tier 2. The authors declare no competing financial interests. Funding Information: We are indebted to Dr. H. Krokan, T. Honjo, and R. Casellas for mouse strains, Dr. I. Lossos for DLB CL cell lines and advice in mouse tumor analysis, M. Cawthorn for technical assistance with mice, D. Fillon and S. Methot for help with confocal microscopy and image analysis, S. Terouz for histological preparations, the University of Miami Sylvester Cancer Center Oncogenomics facility for DNA sequencing assistance, Dr. D. Mu?oz for advice on AID IHC, and Dr. J. Karlseder, Dr. N. Francis, and Dr. C. Rada for comments on the manuscript. This work was supported by grants from the National Institute of Allergy and Infectious Diseases (R56-AI106894-01A1), the Miami Center for AIDS Research (1P30AI073961 to R.E. Verdun), and the Canadian Institutes of Health Research (MOP130535 to J.M. Di Noia). J.M. Di Noia holds a Canada Research Chair tier 2. The authors declare no competing financial interests. Publisher Copyright: {\textcopyright} 2016 Cortizas et al.",
year = "2016",
month = oct,
day = "17",
doi = "10.1084/jem.20160635",
language = "English (US)",
volume = "213",
pages = "2459--2472",
journal = "Journal of Experimental Medicine",
issn = "0022-1007",
publisher = "Rockefeller University Press",
number = "11",
}