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PMID: 22312109 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

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

The Journal of experimental medicine ·Vol. 209 ·No. 2 ·2012-02-13 ·Pages 291-305

Du L, Peng R, Björkman A, Filipe de Miranda N, Rosner C, Kotnis A, Berglund M, Liu C, Rosenquist R, Enblad G, Sundström C, Hojjat-Farsangi M, Rabbani H, Teixeira MR, Revy P, Durandy A, Zeng Y, Gennery AR, de Villartay JP, Pan-Hammarström Q

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.

MeSH Terms
Abnormalities, Multiple/genetics DNA End-Joining Repair/genetics,physiology DNA Primers/genetics DNA Repair Enzymes/deficiency,genetics DNA-Binding Proteins/deficiency,genetics Humans Immunoglobulin A/genetics Immunoglobulin Class Switching/genetics,physiology Immunoglobulin Heavy Chains/genetics In Situ Hybridization, Fluorescence Laser Capture Microdissection Lymphoma, B-Cell/genetics Male Mass Spectrometry Mutagenesis Mutation, Missense/genetics Polymerase Chain Reaction Reverse Transcriptase Polymerase Chain Reaction Sequence Analysis, DNA Translocation, Genetic/genetics
Chemicals
DNA Primers DNA-Binding Proteins Immunoglobulin A Immunoglobulin Heavy Chains NHEJ1 protein, human DNA Repair Enzymes
Authors & Affiliations
20 authors, click to expand affiliations / ORCID
Du Likun
Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, Huddinge, SE-14186 Stockholm, Sweden.
Peng Roujun
Björkman Andrea
Filipe de Miranda Noel
Rosner Cornelia
Kotnis Ashwin
Berglund Mattias
Liu Chonghai
Rosenquist Richard
Enblad Gunilla
Sundström Christer
Hojjat-Farsangi Mohammad
Rabbani Hodjattallah
Teixeira Manuel R
Revy Patrick
Durandy Anne
Zeng Yixin
Gennery Andrew R
de Villartay Jean-Pierre
Pan-Hammarström Qiang
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Article Info
Journal
The Journal of experimental medicine
Abbr.
J Exp Med
ISSN
1540-9538
DOI
10.1084/jem.20110325
Published
2012-02-13
Epub
2012-00-06
Pages
291-305
Language
English
Region
United States
NLM ID
2985109R
PMCID
PMC3280866
Subset
IM
Grants
European Research Council · 242551 · International
External Links
PubMed source DOI: 10.1084/jem.20110325 PMC Full Text View journal details
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