Immunoglobulin somatic hypermutation.

  title={Immunoglobulin somatic hypermutation.},
  author={Grace Teng and Fotini Nina Papavasiliou},
  journal={Annual review of genetics},
The immunoglobulin (Ig) repertoire achieves functional diversification through several somatic alterations of the Ig locus. One of these processes, somatic hypermutation (SHM), deposits point mutations into the variable region of the Ig gene to generate higher-affinity variants. Activation-induced cytidine deaminase (AID) converts cytidine to uridine to initiate the hypermutation process. Error-prone versions of DNA repair are believed to then process these lesions into a diverse spectrum of… 

Figures from this paper

The biochemistry of somatic hypermutation.

Activation-induced cytidine deaminase is the first of a complex series of proteins that introduce point mutations into variable regions of the Ig genes and regulated on many levels by complex mechanisms that are only beginning to be elucidated.

Diversification of the immunoglobulin genes: analysis of the molecular mechanisms in the chicken B cell line DT40

The main goal of the work was the examination of the locus specificity of the immunoglobulin somatic hypermutation in the model system DT40, finding a 200 bp DNA-fragment which is both necessary and sufficient to confer the HM activity.

Nonimmunoglobulin target loci of activation-induced cytidine deaminase (AID) share unique features with immunoglobulin genes

To identify as-yet-unknown AID targets, early AID-induced DNA breaks are screened by using two independent genome-wide approaches and a set of unique genes are identified and it is confirmed that these loci accumulated mutations as frequently as Ig locus after AID activation.

Three‐dimensional architecture of the IgH locus facilitates class switch recombination

It is recounted how transcription across S DNA promotes accumulation of RNA polymerase II, leading to the introduction of activating chromatin modifications and hyperaccessible chromatin that is amenable to AID activity.

AID-Targeting and Hypermutation of Non-Immunoglobulin Genes Does Not Correlate with Proximity to Immunoglobulin Genes in Germinal Center B Cells

It is concluded that proximity to Ig loci is unlikely to be a major determinant of AID targeting or mutation of non-Ig genes, and that the MYC transgenes are either missing important regulatory elements that allow mutation or are unable to mutate because their new nuclear position is not conducive to AID deamination.



Targeting of somatic hypermutation

This work reviews and attempts to reconcile the numerous and sometimes conflicting studies on the targeting of SHM to immunoglobulin loci, and highlights areas that hold promise for further investigation.

Targeting of non-Ig sequences in place of the V segment by somatic hypermutation.

It is shown, using mice containing single or multiple transgene constructs, that an immunoglobulin V kappa segment can be replaced by human beta-globin or prokaryotic neo or gpt genes without affecting the rate of hypermutation.

AID Mediates Hypermutation by Deaminating Single Stranded DNA

It is demonstrated that purified, tetrameric AID can deaminate cytidine residues in DNA, but not in RNA, which implies a direct, functional link between hypermutation and transcription.

A/T-targeted somatic hypermutation: critique of the mainstream model.

Human uracil–DNA glycosylase deficiency associated with profoundly impaired immunoglobulin class-switch recombination

It is shown that recessive mutations of the gene encoding uracil–DNA glycosylase (UNG) are associated with profound impairment in CSR at a DNA precleavage step and with a partial disturbance of the SHM pattern in three patients with hyper-IgM syndrome.

Requirement of the Activation-Induced Deaminase (AID) Gene for Immunoglobulin Gene Conversion

It is shown that the disruption of the AID gene in the chicken B cell line DT40 completely blocks Ig gene conversion and that this block can be complemented by reintroduction of theAID complementary DNA, demonstrating that the AIDs master gene controls all B cell–specific modifications of vertebrate Ig genes.

Mutation of BCL-6 gene in normal B cells by the process of somatic hypermutation of Ig genes.

Significant mutations were not observed in c-MYC, S14, or alpha-fetoprotein genes, but BCL-6 was highly mutated in a large proportion of memory B cells of normal individuals, and the mutation pattern was similar to that of Ig genes.

Altering the pathway of immunoglobulin hypermutation by inhibiting uracil-DNA glycosylase

Exercise in DT40 cells of a bacteriophage-encoded protein that inhibits uracil-DNA glycosylase shifts the pattern of IgV gene mutations from transversion dominance to transition dominance, providing good evidence that antibody diversification involves dC → dU deamination within the immunoglobulin locus itself.