Reflections on the state of play in somatic hypermutation.
Somatic hypermutation (SHM) of rearranged variable genes proceeds in two phases. Phase I which is well understood is triggered by activation-induced cytidine deaminase (AID) and targets mutations at C:G base pairs equally on both DNA strands. Phase II, is less well understood, and targets A:T base pairs by co-opting DNA polymerase-eta and acts in a strand biased fashion such that mutations off A exceed mutations of T by two- to threefold. Current molecular models attempting to explain A:T targeted Phase II are critically reviewed. It is the author's viewpoint that the 'RT-model', which invokes both transcription-coupled DNA and RNA deamination together with error-prone reverse transcription via Pol-eta, is the best explanation of current somatic hypermutation data.
Steele
Edward J
EJ
D001482:Base Composition; D003564:Cytidine Deaminase / Q000378:metabolism; D004247:DNA / Q000235:genetics / Q000378:metabolism; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism; D003641:Deamination; D006801:Humans; D027041:Somatic Hypermutation, Immunoglobulin / Q000235:genetics*; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D000099270:Y-Family DNA Polymerases
D003564:Cytidine Deaminase; D004247:DNA; D004259:DNA-Directed DNA Polymerase; D000098830:AICDA (Activation-Induced Cytidine Deaminase); C112338:Rad30 protein; D000099270:Y-Family DNA Polymerases