Interference of mismatch and base excision repair during the processing of adjacent U/G mispairs may play a key role in somatic hypermutation.
In eukaryotic mismatch repair (MMR), degradation of the error-containing strand initiates at nicks or gaps that can be up to a kilobase away from the mispair. These discontinuities may be the ends of Okazaki fragments or the 3'-termini of the leading strands during replication, whereas the termini of invading strands may fulfill this role during recombination. Here we show that, in extracts of human cells, MMR can initiate also at sites of ongoing base excision repair. Although unlikely under normal circumstances, this situation may arise in vivo during somatic hypermutation (SHM) and class switch recombination of Ig genes, where activation-induced cytidine deaminase (AID) generates multiple U/G mismatches in the variable or switch regions. Uracil should normally be excised by base excision repair (BER), but we show here that MMR proteins activated by a nearby mismatch interfere with uracil processing to generate long single-stranded gaps. We postulate that, in a subset of the repair events, filling-in of the MMR-generated gaps might be catalyzed by the error-prone polymerase-eta, rather than by the high-fidelity polymerase-delta. Because polymerase-eta has a propensity to misinsertions opposite adenine residues, the above mechanism would help explain why SHM affects not only C/G, but also A/T base pairs.
Schanz
Silvia
S
Institute of Molecular Cancer Research, University of Zurich, Zurich, Switzerland.
Castor
Dennis
D
Fischer
Franziska
F
Jiricny
Josef
J
D003564:Cytidine Deaminase; D053843:DNA Mismatch Repair; D004260:DNA Repair; D004259:DNA-Directed DNA Polymerase; D005803:Genes, Immunoglobulin; D006151:Guanosine; D006801:Humans; D017578:Immunoglobulin Class Switching / Q000235:genetics; D011995:Recombination, Genetic; D027041:Somatic Hypermutation, Immunoglobulin / Q000235:genetics*; D014498:Uracil; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D000099270:Y-Family DNA Polymerases
D003564:Cytidine Deaminase; D004259:DNA-Directed DNA Polymerase; D006151:Guanosine; D014498:Uracil; D000098830:AICDA (Activation-Induced Cytidine Deaminase); C112338:Rad30 protein; D000099270:Y-Family DNA Polymerases