Why does somatic hypermutation by AID require transcription of its target genes?

Adv Immunol. 2014;122:253-77. doi: 10.1016/B978-0-12-800267-4.00007-9.

Abstract

In this review, I discuss the currently available experimental evidence concerning the molecular interactions of the activation-induced cytidine deaminase (AID) with transcription of its target genes. The basic question that underlies the transcription relationship is how the process of somatic hypermutation of Ig genes can be restricted to their variable (V) regions. This hallmark of SHM assures that high affinity antibodies can be created while the biological functions of their constant (C) region are undisturbed. I present a revised model of AID function in somatic hypermutation (SHM): In a B cell that produces AID protein and undergoes mutation of the V regions of the expressed Ig heavy and light chain genes, only some of the transcription complexes initiating at the active V-region promoters are associated with AID. When AID travels with the elongating RNA polymerase (pol), it attracts proteins that cause the pausing/stalling of pol and termination of transcription, followed by termination of SHM. This differential AID loading model would allow the mutating B cell to continue producing full-length Ig proteins that are required to avoid apoptosis by permitting the cell to assemble functional B cell receptors.

Keywords: AID; AID targets; Hotspots; Negative supercoils; SHM of non-Ig genes; Single-stranded DNA; Somatic hypermutation model; Transcription.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • B-Lymphocyte Subsets / immunology
  • Cytidine Deaminase / biosynthesis
  • Cytidine Deaminase / deficiency
  • Cytidine Deaminase / physiology*
  • Gene Targeting / methods*
  • Humans
  • Immunoglobulin Heavy Chains / genetics
  • Immunoglobulin Light Chains / genetics
  • Lymphocyte Activation / genetics
  • Lymphocyte Activation / immunology
  • Mice
  • Mutation
  • Somatic Hypermutation, Immunoglobulin / genetics*
  • Somatic Hypermutation, Immunoglobulin / immunology*
  • Transcriptional Activation / genetics
  • Transcriptional Activation / immunology*

Substances

  • Immunoglobulin Heavy Chains
  • Immunoglobulin Light Chains
  • AICDA (activation-induced cytidine deaminase)
  • Cytidine Deaminase