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Related Experiment Videos

Enhancers of hypermutation

J Bachl1, M Wabl

  • 1Department of Microbiology and Immunology, University of California, San Francisco, CA 94143-0670, USA.

Immunogenetics
|January 1, 1996
PubMed
Summary

The immunoglobulin heavy chain 3' enhancer is crucial for hypermutation, a process that significantly elevates mutation rates in immunoglobulin genes. This element drives hypermutation independently of its transcriptional enhancement function.

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Area of Science:

  • Immunology
  • Molecular Biology
  • Genetics

Background:

  • Immunoglobulin (Ig) hypermutation dramatically increases mutation rates at Ig loci, exceeding spontaneous rates by over 10^5-fold.
  • Understanding the cis-acting elements regulating this process is key to deciphering Ig gene diversification.

Purpose of the Study:

  • To investigate the roles of 3' enhancers and promoters in immunoglobulin gene hypermutation.
  • To determine if transcriptional enhancement activity is required for hypermutation.

Main Methods:

  • Transfection of a rearranged immunoglobulin mu heavy chain (Igm) gene construct into a cell line with an active Ig mutator.
  • Assessing hypermutation rates with and without the 3' heavy (H) chain enhancer.
  • Replacing the 3' H enhancer with elements of similar function.
  • Substituting the endogenous Ig promoter with the tk promoter.

Main Results:

  • The 3' H enhancer is essential for achieving hypermutation rates comparable to endogenous genes.
  • Hypermutation occurs at a lower, but still elevated, rate in the absence of the 3' enhancer.
  • Alternative elements with enhancer function also support full hypermutation.
  • Hypermutation is not driven by increased transcription rates associated with the 3' enhancer.
  • The tk promoter slightly increased hypermutability, suggesting Ig promoter sequences are not specific targets.

Conclusions:

  • The immunoglobulin heavy chain 3' enhancer plays a critical role in mediating hypermutation.
  • The mechanism of hypermutation driven by the 3' enhancer is distinct from its transcriptional activation function.
  • Specific promoter sequences are unlikely to be the primary determinants for targeting hypermutation.

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