Title

Deletion of the nucleotide excision repair gene Ercc1 reduces immunoglobulin class switching and alters mutations near switch recombination junctions

UMMS Affiliation

Department of Molecular Genetics and Microbiology

Date

8-2-2004

Document Type

Article

Subjects

Animals; Base Pair Mismatch; DNA Repair; DNA-Binding Proteins; Endonucleases; *Immunoglobulin Class Switching; Mice; Mice, Inbred C57BL; MutS Homolog 2 Protein; Mutation; Proto-Oncogene Proteins; *Recombination, Genetic

Disciplines

Life Sciences | Medicine and Health Sciences | Women's Studies

Abstract

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 Smicro segments and recombined Smicro-Sgamma3 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.

Rights and Permissions

Citation: J Exp Med. 2004 Aug 2;200(3):321-30. Epub 2004 Jul 26. Link to article on publisher's site

Related Resources

Link to article in PubMed

PubMed ID

15280420