Cutting edge: DGYW/WRCH is a better predictor of mutability at G:C bases in Ig hypermutation than the widely accepted RGYW/WRCY motif and probably reflects a two-step activation-induced cytidine deaminase-triggered process.
A feature of Ig hypermutation is the presence of hypermutable DNA sequences that are preferentially found in the V regions of Ig genes. Among these, RGYW/WRCY is the most pronounced motif (G:C is a mutable position; R=A/G, Y=C/T, and W=A/T). However, a molecular basis for the high mutability of RGYW was not known until recently. The discovery that activation-induced cytidine deaminase targets the DNA encoding V regions, has enabled the analysis of its targeting properties when expressed outside of the context of hypermutation. We analyzed these data and found evidence that activation-induced cytidine deaminase is the major source of the RGYW mutable motif, but with a new twist: DGYW/WRCH (G:C is the mutable position; D=A/G/T, H=T/C/A) is a better descriptor of the Ig mutation hotspot than RGYW/WRCY. We also found evidence that a DNA repair enzyme may play a role in modifying the sequence of hypermutation hotspots.
Rogozin
Igor B
IB
National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD 20894, USA. rogozin@ncbi.nlm.nih.gov
Diaz
Marilyn
M
D020816:Amino Acid Motifs / Q000235:genetics; D000818:Animals; D001483:Base Sequence / Q000235:genetics; D003564:Cytidine Deaminase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D003596:Cytosine; D045647:DNA Glycosylases / Q000378:metabolism; D004252:DNA Mutational Analysis; D004260:DNA Repair / Q000235:genetics; D006147:Guanine; D006801:Humans; D008213:Lymphocyte Activation / Q000235:genetics*; D011237:Predictive Value of Tests; D027041:Somatic Hypermutation, Immunoglobulin
D006147:Guanine; D003596:Cytosine; D045647:DNA Glycosylases; D003564:Cytidine Deaminase