The concerted action of Msh2 and UNG stimulates somatic hypermutation at A . T base pairs.
Mismatch repair plays an essential role in reducing the cellular mutation load. Paradoxically, proteins in this pathway produce A . T mutations during the somatic hypermutation of immunoglobulin genes. Although recent evidence implicates the translesional DNA polymerase eta in producing these mutations, it is unknown how this or other translesional polymerases are recruited to immunoglobulin genes, since these enzymes are not normally utilized in conventional mismatch repair. In this report, we demonstrate that A . T mutations were closely associated with transversion mutations at a deoxycytidine. Furthermore, deficiency in uracil-N-glycolase (UNG) or mismatch repair reduced this association. These data reveal a previously unknown interaction between the base excision and mismatch repair pathways and indicate that an abasic site generated by UNG within the mismatch repair tract recruits an error-prone polymerase, which then introduces A . T mutations. Our analysis further indicates that repair tracts typically are approximately 200 nucleotides long and that polymerase eta makes approximately 1 error per 300 T nucleotides. The concerted action of Msh2 and UNG in stimulating A . T mutations also may have implications for mutagenesis at sites of spontaneous cytidine deamination.
Frieder
Darina
D
Department of Immunology, University of Toronto, Medical Sciences Building, Toronto, Canada.
Larijani
Mani
M
Collins
Cathy
C
Shulman
Marc
M
Martin
Alberto
A
D000225:Adenine / Q000378:metabolism*; D000818:Animals; D020029:Base Pairing / Q000235:genetics*; D003564:Cytidine Deaminase / Q000378:metabolism; D053843:DNA Mismatch Repair / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007136:Immunoglobulins / Q000235:genetics; D051379:Mice; D008954:Models, Biological; D051718:MutS Homolog 2 Protein / Q000378:metabolism*; D016296:Mutagenesis / Q000187:drug effects; D009154:Mutation / Q000235:genetics; D027041:Somatic Hypermutation, Immunoglobulin / Q000187:drug effects / Q000235:genetics*; D013941:Thymine / Q000378:metabolism*; D051981:Uracil-DNA Glycosidase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
D004791:Enzyme Inhibitors; D007136:Immunoglobulins; D051981:Uracil-DNA Glycosidase; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase; C497173:Msh2 protein, mouse; D051718:MutS Homolog 2 Protein; D000225:Adenine; D013941:Thymine