Premium
Cis‐acting sequences that affect somatic hypermutation of Ig genes
Author(s) -
Slorb Liquid,
Peters Andrew,
Klotz Emily,
Kirn Nayun,
Shen Hong Ming,
Hackett John,
Rogerson Brian,
Martin Terence E.
Publication year - 1998
Publication title -
immunological reviews
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.839
H-Index - 223
eISSN - 1600-065X
pISSN - 0105-2896
DOI - 10.1111/j.1600-065x.1998.tb01438.x
Subject(s) - somatic hypermutation , biology , genetics , gene , enhancer , microbiology and biotechnology , mutation , transcription factor , b cell , antibody
Summary: We review our studies on the mechanism of somatic hypermutation of immunoglobulin genes. Most experiments were carried out using Ig transgenes. We showed in these experiments that all required cisacting elements are present within the 10–16 kb of a cransgene. Only the Ig variable region and its proximate flanks are mutated, not the constant region. Several Ig gene enhancers are permissive for somatic mutation. Association of the enhancer with its natural Ig promoter is not necessary. However, the mutation process seems specific for Ig genes. No mutations were found in housekeeping genes from cells with high levels of somatic hypermutation of their Ig genes. The Ig enhancers may provide the Ig gene specificity. An exception may he the BCL6 gene, which was mutated in but not hut not in mouse B cells Transcription of a region is required for its mutability When the transcriptional promoter located upstream of the variable region is duplicated upstream of the constant region, this region also becomes mutable. This suggests a model in which a mutator factor associates with the RNA polymerase at the promoter, travels with the polymerase during elongation, and causes mutations during polymerase pausing. The DNA repair systems, nucleotide excision repair and DNA mismatch repair, are not required. Our recent data with an artificial substrate of somatic mutation suggest that pausing may be due to secondary structure of the DNA or nascent RNA, and the specific mutations to preferences of the mutator factor.