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Cernunnos influences human immunoglobulin class switch recombination and may be associated with B cell lymphomagenesis

Lookup NU author(s): Professor Andrew GenneryORCiD

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Abstract

Cernunnos is involved in the nonhomologous end-joining (NHEJ) process during DNA double-strand break (DSB) repair. Here, we studied immunoglobulin (Ig) class switch recombination (CSR), a physiological process which relies on proper repair of the DSBs, in B cells from Cernunnos-deficient patients. The pattern of in vivo generated CSR junctions is altered in these cells, with unusually long microhomologies and a lack of direct end-joining. The CSR junctions from Cernunnos-deficient patients largely resemble those from patients lacking DNA ligase IV, Artemis, or ATM, suggesting that these factors are involved in the same end-joining pathway during CSR. By screening 269 mature B cell lymphoma biopsies, we also identified a somatic missense Cernunnos mutation in a diffuse large B cell lymphoma sample. This mutation has a dominant-negative effect on joining of a subset of DNA ends in an in vitro NHEJ assay. Translocations involving both Ig heavy chain loci and clonal-like, dynamic IgA switching activities were observed in this tumor. Collectively, our results suggest a link between defects in the Cernunnos-dependent NHEJ pathway and aberrant CSR or switch translocations during the development of B cell malignancies.

Publication metadata

Author(s): Du LK, Peng RJ, Bjorkman A, de Miranda NF, Rosner C, Kotnis A, Berglund M, Liu CH, Rosenquist R, Enblad G, Sundstrom C, Hojjat-Farsangi M, Rabbani H, Teixeira MR, Revy P, Durandy A, Zeng YX, Gennery AR, de Villartay JP, Pan-Hammarstrom Q

Publication type: Article

Publication status: Published

Journal: Journal of Experimental Medicine

Year: 2012

Volume: 209

Issue: 2

Pages: 291-305

Print publication date: 06/02/2012

ISSN (print): 0022-1007

ISSN (electronic): 1540-9538

Publisher: Rockefeller University Press

URL: http://dx.doi.org/10.1084/jem.20110325

DOI: 10.1084/jem.20110325

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