Decrease in topoisomerase I is responsible for activation-induced cytidine deaminase (AID)-dependent somatic hypermutation

Maki Kobayashi, Zahra Sabouri, Somayeh Sabouri, Yoko Kitawaki, Yves Pommier, Takaya Abe, Hiroshi Kiyonari, Tasuku Honjo

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32 Citations (Scopus)

Abstract

Somatic hypermutation (SHM) and class-switch recombination (CSR) of the Ig gene require both the transcription of the locus and the expression of activation-induced cytidine deaminase (AID). During CSR, AID decreases the amount of topoisomerase I (Top1); this decrease alters the DNA structure and induces cleavage in the S region. Similarly, Top1 is involved in transcription-associated mutation at dinucleotide repeats in yeast and in triplet-repeat contraction in mammals. Here, we report that the AID-induced decrease in Top1 is critical for SHM. Top1 knockdown or haploinsufficiency enhanced SHM, whereas Top1 overexpression down-regulated it. A specific Top1 inhibitor, camptothecin, suppressed SHM, indicating that Top1's activity is required for DNA cleavage. Nonetheless, suppression of transcription abolished SHM, even in cells with Top1 knockdown, suggesting that transcription is critical. These results are consistent with a model proposed for CSR and triplet instability, in which transcription-induced non-B structure formation is enhanced by Top1 reduction and provides the target for irreversible cleavage by Top1.We speculate that the mechanismfor transcription-coupled genome instability was adopted to generate immune diversity when AID evolved.

Original languageEnglish
Pages (from-to)19305-19310
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number48
DOIs
Publication statusPublished - 29 Nov 2011
Externally publishedYes

Keywords

  • DNA cleavage
  • Non-B DNA structure

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