The Journal of Experimental Medicine
ThymUS '08
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Published online 26 July 2004 doi:10.1084/jem.20040052
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 200, Number 3, 321-330
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Deletion of the Nucleotide Excision Repair Gene Ercc1 Reduces Immunoglobulin Class Switching and Alters Mutations Near Switch Recombination Junctions

Carol E. Schrader1, Joycelyn Vardo1, Erin Linehan1, Michael Z. Twarog1, Laura J. Niedernhofer2, Jan H.J. Hoeijmakers2, and Janet Stavnezer1

1 Department of Molecular Genetics and Microbiology, Program in Immunology and Virology, University of Massachusetts Medical School, Worcester, MA 01655
2 MGC-Department of Cell Biology and Genetics, Centre for Biomedical Genetics, Erasmus Medical Center, 3000 DR Rotterdam, Netherlands

Address correspondence to Janet Stavnezer, Dept. of Molecular Genetics and Microbiology, University of Massachusetts Medical School, 55 Lake Ave. North, Worcester, MA 01655. Phone: (508) 856-4100; Fax: (508) 856-5920; email: janet.stavnezer{at}umassmed.edu

The structure-specific endonuclease ERCC1-XPF is an essential component of the nucleotide excision DNA repair pathway. ERCC1-XPF nicks double-stranded DNA immediately adjacent to 3' single-strand regions. Substrates include DNA bubbles and flaps. Furthermore, ERCC1 interacts with Msh2, a mismatch repair (MMR) protein involved in class switch recombination (CSR). Therefore, ERCC1-XPF has abilities that might be useful for antibody CSR. We tested whether ERCC1 is involved in CSR and found that Ercc1–/– splenic B cells show moderately reduced CSR in vitro, demonstrating that ERCC1-XPF participates in, but is not required for, CSR. To investigate the role of ERCC1 in CSR, the nucleotide sequences of switch (S) regions were determined. The mutation frequency in germline Sµ segments and recombined Sµ-S{gamma}3 segments cloned from Ercc1–/– splenic B cells induced to switch in culture was identical to that of wild-type (WT) littermates. However, Ercc1–/– cells show increased targeting of the mutations to G:C bp in RGYW/WRCY hotspots and mutations occur at sites more distant from the S–S junctions compared with WT mice. The results indicate that ERCC1 is not epistatic with MMR and suggest that ERCC1 might be involved in processing or repair of DNA lesions in S regions during CSR.

Key Words: ERCC1-XPF • antibody • heavy chain • DNA repair • mouse B cells

L.J. Niedernhofer's present address is Dept. of Molecular Genetics and Biochemistry, University of Pittsburgh, Pittsburgh, PA 15213.

Abbreviations used in this paper: AID, activation-induced cytidine deaminase; BER, base excision repair; CFSE, carboxyfluorescein diacetate succinimidyl ester; CSR, class switch recombination; GL, germline; MMR, mismatch repair; NER, nucleotide excision repair; NHEJ, nonhomologous end joining; S, switch; SHM, somatic hypermutation; UNG, uracil DNA glycosylase.


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