Repair of naturally occurring mismatches can induce mutations in flanking DNA.
'Normal' genomic DNA contains hundreds of mismatches that are generated daily by the spontaneous deamination of C (U/G) and methyl-C (T/G). Thus, a mutagenic effect of their repair could constitute a serious genetic burden. We show here that while mismatches introduced into human cells on an SV40-based episome were invariably repaired, this process induced mutations in flanking DNA at a significantly higher rate than no mismatch controls. Most mutations involved the C of TpC, the substrate of some single strand-specific APOBEC cytidine deaminases, similar to the mutations that can typify the 'mutator phenotype' of numerous tumors. siRNA knockdowns and chromatin immunoprecipitation showed that TpC preferring APOBECs mediate the mutagenesis, and siRNA knockdowns showed that both the base excision and mismatch repair pathways are involved. That naturally occurring mispairs can be converted to mutators, represents an heretofore unsuspected source of genetic changes that could underlie disease, aging, and evolutionary change.DOI: http://dx.doi.org/10.7554/eLife.02001.001.
Section on Genomic Structure and Function, Laboratory of Cell and Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, United States.
Jia
J
Chen
Section on Genomic Structure and Function, Laboratory of Cell and Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, United States.
Brendan F
BF
Miller
Section on Genomic Structure and Function, Laboratory of Cell and Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, United States avf@helix.nih.gov.
Anthony V
AV
Furano
D020137:Base Pair Mismatch; D047369:Chromatin Immunoprecipitation; D003564:Cytidine Deaminase; D004247:DNA / Q000737:chemistry / Q000235:genetics*; D004260:DNA Repair; D006801:Humans; D015778:Minor Histocompatibility Antigens; D009154:Mutation; D034741:RNA, Small Interfering / Q000235:genetics; D013539:Simian virus 40 / Q000235:genetics
D015778:Minor Histocompatibility Antigens; D034741:RNA, Small Interfering; D004247:DNA; C495794:APOBEC3B protein, human; D003564:Cytidine Deaminase
APOBEC deaminase; DNA repair; mutagenesis