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Altered somatic hypermutation and reduced class-switch recombination in exonuclease 1–mutant mice


The generation of protective antibodies requires somatic hypermutation (SHM) and class-switch recombination (CSR) of immunoglobulin genes. Here we show that mice mutant for exonuclease 1 (Exo1), which participates in DNA mismatch repair (MMR), have decreased CSR and changes in the characteristics of SHM similar to those previously observed in mice mutant for the MMR protein Msh2. Exo1 is thus the first exonuclease shown to be involved in SHM and CSR. The phenotype of Exo1−/− mice and the finding that Exo1 and Mlh1 are physically associated with mutating variable regions support the idea that Exo1 and MMR participate directly in SHM and CSR.

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This work was supported by grants from the US National Institutes of Health: 5T32 CA 09173 (P.D.B.), T326 MO 7491 (C.J.W.), CA 76329 and CA 93484 (W.E.), AI 53362, CA102705 and CA72649 (M.D.S.). A.M. and Z.L. are recipients of Cancer Research Institute Fellowships and A.M. is currently a Special Fellow from the Leukemia and Lymphoma Society. W.E. is also supported by the Irma T. Hirschl Career Scientist Award. M.D.S. has the additional support of the Harry Eagle Chair provided by the Women's Division of the Albert Einstein College of Medicine.

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The authors declare no competing financial interests.

Correspondence to Matthew D Scharff.

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Figure 1: FACS analysis of in vitro–switched splenocytes.
Figure 2: Serum ELISA of anti-NP immunoglobulin response.
Figure 3: Mutation analysis of the immunoglobulin gene.
Figure 4: Chromatin immunoprecipitation (ChIP) experiments for Exo1 and Mlh1 in the BL2 Burkitt's lymphoma cell line.