Cernunnos influences human immunoglobulin class switch recombination and may be associated with B cell lymphomagenesis.
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.
Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, Huddinge, SE-14186 Stockholm, Sweden.
Likun
L
Du
Roujun
R
Peng
Andrea
A
Björkman
Noel
N
Filipe de Miranda
Cornelia
C
Rosner
Ashwin
A
Kotnis
Mattias
M
Berglund
Chonghai
C
Liu
Richard
R
Rosenquist
Gunilla
G
Enblad
Christer
C
Sundström
Mohammad
M
Hojjat-Farsangi
Hodjattallah
H
Rabbani
Manuel R
MR
Teixeira
Patrick
P
Revy
Anne
A
Durandy
Yixin
Y
Zeng
Andrew R
AR
Gennery
Jean-Pierre
JP
de Villartay
Qiang
Q
Pan-Hammarström
D000015:Abnormalities, Multiple / Q000235:genetics*; D059766:DNA End-Joining Repair / Q000235:genetics / Q000502:physiology*; D017931:DNA Primers / Q000235:genetics; D045643:DNA Repair Enzymes / Q000172:deficiency* / Q000235:genetics; D004268:DNA-Binding Proteins / Q000172:deficiency* / Q000235:genetics; D006801:Humans; D007070:Immunoglobulin A / Q000235:genetics; D017578:Immunoglobulin Class Switching / Q000235:genetics / Q000502:physiology*; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D017404:In Situ Hybridization, Fluorescence; D061346:Laser Capture Microdissection; D016393:Lymphoma, B-Cell / Q000235:genetics*; D008297:Male; D013058:Mass Spectrometry; D016296:Mutagenesis; D020125:Mutation, Missense / Q000235:genetics; D016133:Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D014178:Translocation, Genetic / Q000235:genetics*
D017931:DNA Primers; D004268:DNA-Binding Proteins; D007070:Immunoglobulin A; D007143:Immunoglobulin Heavy Chains; C508551:NHEJ1 protein, human; D045643:DNA Repair Enzymes