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Targeting Of Somatic Hypermutation By immunoglobulin Enhancer And Enhancer-Like Sequences

2014; Public Library of Science; Volume: 12; Issue: 4 Linguagem: Inglês

10.1371/journal.pbio.1001831

1545-7885

Jean-Marie Buerstedde, Jukka Alinikula, Hiroshi Arakawa, Jessica J. McDonald, David G. Schatz,

Toxin Mechanisms and Immunotoxins

Somatic hypermutation (SH) generates point mutations within rearranged immunoglobulin (Ig) genes of activated B cells, providing genetic diversity for the affinity maturation of antibodies. SH requires the activation-induced cytidine deaminase (AID) protein and transcription of the mutation target sequence, but how the Ig gene specificity of mutations is achieved has remained elusive. We show here using a sensitive and carefully controlled assay that the Ig enhancers strongly activate SH in neighboring genes even though their stimulation of transcription is negligible. Mutations in certain E-box, NFκB, MEF2, or Ets family binding sites—known to be important for the transcriptional role of Ig enhancers—impair or abolish the activity. Full activation of SH typically requires a combination of multiple Ig enhancer and enhancer-like elements. The mechanism is evolutionarily conserved, as mammalian Ig lambda and Ig heavy chain intron enhancers efficiently stimulate hypermutation in chicken cells. Our results demonstrate a novel regulatory function for Ig enhancers, indicating that they either recruit AID or alter the accessibility of the nearby transcription units.