| First Author | Sharbeen G | Year | 2010 |
| Journal | Nucleic Acids Res | Volume | 38 |
| Issue | 22 | Pages | 8120-30 |
| PubMed ID | 20705648 | Mgi Jnum | J:286661 |
| Mgi Id | MGI:6212274 | Doi | 10.1093/nar/gkq682 |
| Citation | Sharbeen G, et al. (2010) Incorporation of dUTP does not mediate mutation of A:T base pairs in Ig genes in vivo. Nucleic Acids Res 38(22):8120-30 |
| abstractText | Activation-induced cytidine deaminase (AID) protein initiates Ig gene mutation by deaminating cytosines, converting them into uracils. Excision of AID-induced uracils by uracil-N-glycosylase is responsible for most transversion mutations at G:C base pairs. On the other hand, processing of AID-induced G:U mismatches by mismatch repair factors is responsible for most mutation at Ig A:T base pairs. Why mismatch processing should be error prone is unknown. One theory proposes that long patch excision in G1-phase leads to dUTP-incorporation opposite adenines as a result of the higher G1-phase ratio of nuclear dUTP to dTTP. Subsequent base excision at the A:U base pairs produced could then create non-instructional templates leading to permanent mutations at A:T base pairs (1). This compelling theory has remained untested. We have developed a method to rapidly modify DNA repair pathways in mutating mouse B cells in vivo by transducing Ig knock-in splenic mouse B cells with GFP-tagged retroviruses, then adoptively transferring GFP(+) cells, along with appropriate antigen, into primed congenic hosts. We have used this method to show that dUTP-incorporation is unlikely to be the cause of AID-induced mutation of A:T base pairs, and instead propose that A:T mutations might arise as an indirect consequence of nucleotide paucity during AID-induced DNA repair. |
