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Review
. 2007 Jan 22;204(1):7-10.
doi: 10.1084/jem.20062409. Epub 2006 Dec 26.

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

Michael S Neuberger  1 , Cristina Rada
Affiliations
Review

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

Michael S Neuberger et al. J Exp Med. .

Abstract

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 eta.

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Figures

Figure 1.
Figure 1.
(A) A model for the major pathways of somatic hypermutation in normal mice. After AID-catalyzed C→U deamination, the resulting U/G mispair is recognized by either UNG or MSH2–MSH6. (Mutations at C/G pairs) UNG-mediated recognition leads to the generation of an abasic site. Replication across this abasic site (by REV1 and other translesion polymerases) results in the generation of both transition and transversion substitutions at C/G pairs. (Mutations at A/T pairs) MSH2–MSH6-mediated recognition of the U/G mispair triggers an exonuclease I– and polymerase η–dependent patch repair process which results in mutations at A/T pairs. (B) Backup pathways that may operate in mutant mice. In the absence of UNG, replication across the U/G lesion leads solely to transition mutations at C/G pairs (the extent to which transitions at C/G are normally attributable to replication across the uracil as opposed to across the abasic site is unknown). In the absence of polymerase η, MSH2–MSH6 appears to recruit a backup polymerase that yields some residual mutations at A/T pairs. In the absence of MSH2, replication across the UNG-generated abasic site can also involve a mutagenic polymerase η–dependent patch repair process that generates mutations at A/T pairs. However, in the absence of polymerase η, no other polymerase is able to substitute for mutation creation at A/T pairs in this UNG-dependent pathway.
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