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Assessing Somatic Hypermutation in Ramos B Cells after Overexpression or Knockdown of Specific Genes
Published on: November 1, 2011
Cis-acting sequences that affect somatic hypermutation of Ig genes
1Department of Molecular Genetics and Cell Biology, University of Chicago 60637, Illinois, USA. stor@midway.uchicago.edu
Immunological Reviews
|May 29, 1998
Summary
Somatic hypermutation targets immunoglobulin genes specifically, driven by enhancers and transcription. A mutator factor associates with RNA polymerase, causing mutations during pauses, independent of DNA repair systems.
Area of Science:
- Immunology
- Molecular Biology
- Genetics
Background:
- Somatic hypermutation (SHM) is crucial for antibody diversity.
- Understanding the cis-acting elements and regulatory mechanisms of SHM is essential.
Purpose of the Study:
- To elucidate the molecular mechanisms governing somatic hypermutation of immunoglobulin genes.
- To identify the factors and processes involved in the specificity and regulation of SHM.
Main Methods:
- Experiments utilizing immunoglobulin (Ig) transgenes.
- Analysis of mutations in Ig variable regions and flanking sequences.
- Investigating the role of Ig enhancers and promoters.
- Assessing the requirement for transcription and DNA repair pathways.
Main Results:
- All necessary cis-acting elements for SHM are located within 10-16 kb of the Ig transgene.
- Only the Ig variable region and its immediate flanks are mutated, not the constant region.
- Ig enhancers are permissive for SHM, independent of their natural Ig promoter.
- SHM is specific to Ig genes, with no mutations observed in housekeeping genes.
- Transcription is required for mutability; duplicating a promoter upstream of the constant region renders it mutable.
- Nucleotide excision repair and DNA mismatch repair are not required for SHM.
- A model involving a mutator factor associating with RNA polymerase during transcription elongation and pausing is proposed.
Conclusions:
- SHM is a transcription-dependent process regulated by Ig enhancers.
- A mutator factor, potentially influenced by DNA/RNA secondary structures, mediates mutations during polymerase pausing.
- The process is distinct from canonical DNA repair pathways.
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