title: Decrease in topoisomerase I is responsible for activation-induced cytidine deaminase (AID)-dependent somatic hypermutation.
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.
authors.affiliation: Department of Immunology and Genomic Medicine, Graduate School of Medicine,  Kyoto University, Kyoto 606-8501,  Japan.
authors.forename: Maki
authors.initials: M
authors.lastname: Kobayashi
authors.forename: Zahra
authors.initials: Z
authors.lastname: Sabouri
authors.forename: Somayeh
authors.initials: S
authors.lastname: Sabouri
authors.forename: Yoko
authors.initials: Y
authors.lastname: Kitawaki
authors.forename: Yves
authors.initials: Y
authors.lastname: Pommier
authors.forename: Takaya
authors.initials: T
authors.lastname: Abe
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kiyonari
authors.forename: Tasuku
authors.initials: T
authors.lastname: Honjo
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002166:Camptothecin; D045744:Cell Line, Tumor; D003001:Cloning, Molecular; D003564:Cytidine Deaminase / Q000378:metabolism*; D004264:DNA Topoisomerases, Type I / Q000235:genetics / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D005822:Genetic Vectors / Q000235:genetics; D049452:Green Fluorescent Proteins; D057895:Haploinsufficiency; D006801:Humans; D017578:Immunoglobulin Class Switching / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D027041:Somatic Hypermutation, Immunoglobulin / Q000502:physiology*; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin
references.citation: Nat Rev Genet. 2010 Apr;11(4):247-58
references.pmid: 20177426
references.citation: EMBO J. 1986 Jan;5(1):95-102
references.pmid: 3007121
references.citation: Proc Natl Acad Sci U S A. 1998 Jan 6;95(1):87-9
references.pmid: 9419331
references.citation: Science. 2002 Jun 14;296(5575):2033-6
references.pmid: 12065838
references.citation: J Immunol. 2003 Sep 1;171(5):2504-9
references.pmid: 12928399
references.citation: Cancer Res. 2001 Mar 1;61(5):1964-9
references.pmid: 11280753
references.citation: Nat Cell Biol. 2009 Nov;11(11):1315-24
references.pmid: 19838172
references.citation: Trends Biochem Sci. 2007 Jun;32(6):271-8
references.pmid: 17493823
references.citation: Proc Natl Acad Sci U S A. 2009 Dec 29;106(52):22375-80
references.pmid: 20018730
references.citation: Cell. 2000 Sep 1;102(5):565-75
references.pmid: 11007475
references.citation: Blood. 2003 May 15;101(10):4029-32
references.pmid: 12521993
references.citation: Experientia. 1994 Mar 15;50(3):261-9
references.pmid: 8143800
references.citation: Proc Natl Acad Sci U S A. 2009 Feb 24;106(8):2758-63
references.pmid: 19202055
references.citation: Proc Natl Acad Sci U S A. 2011 Jan 11;108(2):698-703
references.pmid: 21177427
references.citation: Nature. 2001 Dec 6;414(6864):660-665
references.pmid: 11740565
references.citation: Nat Immunol. 2003 Sep;4(9):843-8
references.pmid: 12910268
references.citation: Nat Rev Cancer. 2006 Oct;6(10):789-802
references.pmid: 16990856
references.citation: Cancer Res. 2007 Sep 15;67(18):8752-61
references.pmid: 17875716
references.citation: Cell. 2004 Aug 20;118(4):431-8
references.pmid: 15315756
references.citation: Mol Cell Biol. 1996 Dec;16(12):6804-9
references.pmid: 8943335
references.citation: EMBO J. 2009 Jan 21;28(2):99-111
references.pmid: 19078966
references.citation: Nat Med. 2007 Apr;13(4):470-6
references.pmid: 17401375
references.citation: Proc Natl Acad Sci U S A. 2003 Mar 4;100(5):2634-8
references.pmid: 12591955
references.citation: J Exp Med. 2007 Nov 26;204(12):2989-3001
references.pmid: 17998390
references.citation: J Immunol. 1986 Jun 15;136(12):4695-9
references.pmid: 3086440
references.citation: Mol Immunol. 2007 Feb;44(5):934-42
references.pmid: 16730063
references.citation: Mol Cell. 2003 Aug;12(2):501-8
references.pmid: 14536088
references.citation: Nature. 1986 Dec 11-17;324(6097):585-9
references.pmid: 3491327
references.citation: Nucleic Acids Res. 1997 May 15;25(10):1913-9
references.pmid: 9115357
references.citation: Nature. 2007 Dec 13;450(7172):1106-10
references.pmid: 18033247
references.citation: Mol Immunol. 2008 Aug;45(13):3589-99
references.pmid: 18585784
references.citation: Oncogene. 2007 Aug 16;26(38):5587-95
references.pmid: 17404578
references.citation: J Immunol. 2001 Apr 15;166(8):5051-7
references.pmid: 11290786
references.citation: Cell. 2000 Sep 1;102(5):553-63
references.pmid: 11007474
references.citation: Proc Natl Acad Sci U S A. 2011 Jan 11;108(2):692-7
references.pmid: 21177431
references.citation: Carcinogenesis. 2011 Jan;32(1):110-9
references.pmid: 20974684
references.citation: Front Biosci. 2003 Jan 01;8:d210-21
references.pmid: 12456359
references.citation: J Exp Med. 2002 Feb 18;195(4):529-34
references.pmid: 11854365
references.citation: Nucleic Acids Res. 1990 Sep 11;18(17):5322
references.pmid: 1698283
references.citation: Immunity. 1996 Jan;4(1):57-65
references.pmid: 8574852
references.citation: EMBO J. 2002 Feb 1;21(3):195-201
references.pmid: 11823412
references.citation: Proc Natl Acad Sci U S A. 2010 Dec 21;107(51):22190-5
references.pmid: 21139053
references.citation: J Biol Chem. 2004 Nov 12;279(46):47411-4
references.pmid: 15326170
references.citation: Biochim Biophys Acta. 1991 Jun 13;1089(2):175-82
references.pmid: 2054380
references.citation: EMBO J. 1986 Dec 1;5(12):3259-66
references.pmid: 3028778
references.citation: Clin Cancer Res. 2002 Aug;8(8):2499-504
references.pmid: 12171875
references.citation: Proc Natl Acad Sci U S A. 2005 Mar 22;102(12):4506-11
references.pmid: 15767564
references.citation: Immunity. 1998 Jul;9(1):105-14
references.pmid: 9697840
references.citation: Cell Mol Life Sci. 2010 Jan;67(1):43-62
references.pmid: 19727556
references.citation: Mol Cell Biol. 2011 Aug;31(15):3105-12
references.pmid: 21628532
references.citation: J Exp Med. 2001 Aug 6;194(3):365-74
references.pmid: 11489955
references.citation: Nature. 2008 Feb 14;451(7180):841-5
references.pmid: 18273020
references.citation: Proc Natl Acad Sci U S A. 1987 Oct;84(20):7024-7
references.pmid: 2823250
references.citation: Nat Immunol. 2002 Sep;3(9):815-21
references.pmid: 12145648
references.citation: Curr Opin Genet Dev. 2007 Apr;17(2):88-93
references.pmid: 17307351