Somatic hypermutation: activation-induced deaminase for C/G followed by polymerase η for A/T

Somatic hypermutation (SHM) introduces nucleotide substitutions into immunoglobulin variable (Ig V) region genes at all four bases, but the mutations at C/G and A/T pairs are achieved by distinct mechanisms. Mutations at C/G pairs are a direct consequence of the C→U deamination catalyzed by activation-induced deaminase (AID). Mutations at A/T pairs, however, require a second mutagenic process that occurs during patch repair of the AID-generated U/G mismatch. Several DNA polymerases have been proposed to play a role in SHM, but accumulating evidence indicates that the mutations at A/T are overwhelmingly achieved by recruitment of DNA polymerase η.

• Publication year

  2007

• Venue

  Journal of Experimental Medicine

• Publication date

  2007-01-22

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1084/jem.20062409PMID 17190841PMCID 2118430
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• DNA repair in antibody somatic hypermutation.

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• An update on the role of translesion synthesis DNA polymerases in Ig hypermutation.

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• DNA Polymerase η Contributes to Strand Bias of Mutations of A versus T in Immunoglobulin Genes1

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• Repair and genetic consequences of endogenous DNA base damage in mammalian cells.

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  2004cited by this paper
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  2003cited by this paper
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  2003cited by this paper
• Immunity through DNA deamination.

  2003cited by this paper
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  2001cited by this paper
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  2001cited by this paper
• Class switch recombination and hypermutation require activation-induced cytidine deaminase (AID), a potential RNA editing enzyme.

  2000influential reference
• Activation-induced cytidine deaminase (AID) deficiency causes the autosomal recessive form of the Hyper-IgM syndrome (HIGM2).

  2000cited by this paper
• Efficient bypass of a thymine-thymine dimer by yeast DNA polymerase, Poleta.

  1999cited by this paper
• Hot spot focusing of somatic hypermutation in MSH2-deficient mice suggests two stages of mutational targeting.

  1998cited by this paper
• Brief Definitive Report Strand-biased Defect in C/g Transversions in Hypermutating Immunoglobulin Genes in Rev1-defi Cient Mice

  year unknowncited by this paper
• Brief Definitive Report

  year unknowncited by this paper

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  2013cites this paper
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