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Cernunnos influences human immunoglobulin class switch recombination and may be associated with B cell lymphomagenesis
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- Du, Likun (author)
- Karolinska Institutet
- Peng, Roujun (author)
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- Björkman, Andrea (author)
- Karolinska Institutet
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- Rosner, Cornelia (author)
- Kotnis, Ashwin (author)
- Liu, Chonghai (author)
- Rabbani, Hodjattallah (author)
- Teixeira, Manuel R (author)
- Revy, Patrick (author)
- Durandy, Anne (author)
- Zeng, Yixin (author)
- Gennery, Andrew R (author)
- de Villartay, Jean-Pierre (author)
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- (creator_code:org_t)
- 2012-02-06
- 2012
- English.
- In: Journal of Experimental Medicine. - : Rockefeller University Press. - 0022-1007 .- 1540-9538. ; 209:2, s. 291-305
- Journal article (peer-reviewed)
Abstract
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- 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.
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