Likun Du,
Roujun Peng,
Andrea Björkman,
Noel Filipe de Miranda,
Cornelia Rosner,
Ashwin Kotnis,
Mattias Berglund,
Chonghai Liu,
Richard Rosenquist, Gunilla Enblad,
Christer Sundström,
Mohammad Hojjat-Farsangi,
Hodjattallah Rabbani,
Manuel R. Teixeira,
Patrick Revy,
Anne Durandy,
Yixin Zeng,
Andrew R. Gennery,
Jean-Pierre de Villartay,
Qiang Pan-Hammarström
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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.
Journal of Experimental Medicine 02/2012; 209(2):291-305. · 13.85 Impact Factor
