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Title: Decrease in topoisomerase I is responsible for activation-induced cytidine deaminase (AID)-dependent somatic hypermutation.
Authors: Kobayashi, Maki  kyouindb  KAKEN_id
Sabouri, Zahra
Sabouri, Somayeh
Kitawaki, Yoko
Pommier, Yves
Abe, Takaya
Kiyonari, Hiroshi
Honjo, Tasuku
Author's alias: 本庶, 佑
Issue Date: 29-Nov-2011
Publisher: National Academy of Sciences
Journal title: Proceedings of the National Academy of Sciences of the United States of America
Volume: 108
Issue: 48
Start page: 19305
End page: 19310
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 mechanism for transcription-coupled genome instability was adopted to generate immune diversity when AID evolved.
Rights: ©2012 by the National Academy of Sciences
この論文は出版社版でありません。引用の際には出版社版をご確認ご利用ください。
This is not the published version. Please cite only the published version.
URI: http://hdl.handle.net/2433/152359
DOI(Published Version): 10.1073/pnas.1114522108
PubMed ID: 22080610
Appears in Collections:Journal Articles

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