「体細胞超変異」の版間の差分
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{{翻訳直後|[[:en:Special:Redirect/revision/1001956154|en:Somatic hypermutation]]|date=2021年2月}}
'''体細胞超変異'''（たいさいぼうちょうへんい、{{Lang-en-short|Somatic hypermutation, '''SHM'''}}）もしくは'''体細胞超突然変異'''（たいさいぼうちょうとつぜんへんい）とは、{{仮リンク|適応免疫系|en|Adaptive immune system}}が[[微生物]]などの新しい外来要素に適応する手段の1つで、[[クラススイッチ]]の際などに見られる[[細胞]]メカニズムである。{{仮リンク|親和性成熟|en|Affinity maturation}}の中でも重要な一部であり、外来要素（[[抗原]]）を認識するために使用される[[B細胞]]受容体を多様化し、免疫系が生物個体の一生を通じて新しい脅威へ適応可能とする<ref name="Janeway2005">{{Cite book|last=Janeway, C.A.|last2=Travers, P.|last3=Walport, M.|last4=Shlomchik, M.J.|year=2005|title=Immunobiology|edition=6th|publisher=Garland Science|isbn=978-0-8153-4101-7}}</ref>。[[抗体|免疫グロブリン]]遺伝子の可変領域に影響を与えるプログラム済み[[突然変異]]を伴う。{{仮リンク|生殖細胞系列変異|en|Germline mutation}}とは異なり、SHMは生物の個々の[[リンパ球|免疫細胞]]にのみ影響を及ぼし、子孫に遺伝することはない<ref name="Oprea1999">Oprea, M. (1999) [http://www.santafe.edu/~mihaela/thesis/version_short.html ''Antibody Repertoires and Pathogen Recognition:''] {{Webarchive|url=https://web.archive.org/web/20080906130252/http://www.santafe.edu/~mihaela/thesis/version_short.html|date=2008-09-06}} The Role of Germline Diversity and Somatic Hypermutation'' (Thesis) University of Leeds.''</ref>。{{仮リンク|B細胞リンパ腫|en}}<ref name="Odegard2006">{{Cite journal|last=Odegard V.H.|last2=Schatz D.G.|year=2006|title=Targeting of somatic hypermutation|journal=Nat. Rev. Immunol.|volume=6|issue=8|pages=573–583|DOI=10.1038/nri1896|PMID=16868548}}</ref>その他の多くの癌<ref name=":18">{{Cite journal|last=Steele|first=E.J.|last2=Lindley|first2=R.A.|year=2010|title=Somatic mutation patterns in non-lymphoid cancers resemble the strand biased somatic hypermutation spectra of antibody genes|url=http://researchrepository.murdoch.edu.au/id/eprint/4482/1/Somatic_mutation_patterns.pdf|journal=DNA Repair|volume=9|issue=6|pages=600–603|DOI=10.1016/j.dnarep.2010.03.007|PMID=20418189}}</ref><ref name=":19">{{Cite journal|last=Lindley|first=R.A.|last2=Steele|first2=E.J.|year=2013|title=Critical analysis of strand-biased somatic mutation signatures in TP53 versus Ig genes, in genome -wide data and the etiology of cancer|url=https://www.hindawi.com/journals/isrn/2013/921418/|journal=ISRN Genomics|volume=2013 Article ID 921418|pages=18 pages}}</ref>の発症にメカニズムに誤標的化体細胞超変異が関わっている可能性が高い。
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超変異プロセスは、生物個体自身の細胞の'signature'{{訳語疑問点|date=2021年2月}}に対して自己選択する細胞も利用する。この自己選択プロセスの失敗が{{仮リンク|自己免疫|en|Autoimmunity}}反応の発生につながるという仮説がある<ref>{{Cite journal|last=Metzger|first=T.C.|year=2011|title=Control of Central and Peripheral Tolerance by Aire|journal=Immunol Rev. 2011 May|volume=241|issue=1|pages=89–103|DOI=10.1111/j.1600-065X.2011.01008.x|PMID=21488892|PMC=3093413}}</ref>。
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== モデル ==
Developments on the viability of the two main competing molecular models on the mechanism of somatic hypermutation (SHM) since 1987 have now reached a resolution, particular molecular data published since 2000.
Much of this early phase data has been reviewed by Teng and Papavasiliou<ref name="Teng2007">{{Cite journal|last=Teng, G.|last2=Papavasiliou, F.N.|year=2007|title=Immunoglobulin Somatic Hypermutation|journal=Annu. Rev. Genet.|volume=41|pages=107–120|DOI=10.1146/annurev.genet.41.110306.130340|PMID=17576170}}
=== DNA脱アミノ化モデル ===
、This can be labelled the DNA-based model. It is enzymatically focused solely on DNA substrates.
The modern form, outlined in previous sections is the Neuberger "DNA deamination model" based on activation-induced cytidine deaminase (AID) and short-patch error-prone DNA repair by DNA polymerase-eta operating around AID C-to-U lesions<ref name="Teng2007">{{Cite journal|last=Teng, G.|last2=Papavasiliou, F.N.|year=2007|title=Immunoglobulin Somatic Hypermutation|journal=Annu. Rev. Genet.|volume=41|pages=107–120|DOI=10.1146/annurev.genet.41.110306.130340|PMID=17576170}}
This model only partially explains the origins of the full spectrum of somatic mutations at A:T and G:C base pairs observed in SHM in B lymphocytes in vivo during an antigen-driven immune response.
It also does not logically explain how strand biased mutations may be generated.
A key feature is its critical dependence on the gap-filling error prone DNA repair synthesis properties of DNA polymerase-eta targeting A:T base pairs at AID-mediated C-to-U lesions or ssDNA nicks.<ref name=":7">{{Cite journal|last=Zeng|first=X|last2=Winter|first2=D.B.|last3=Kasmer|first3=C|last4=Kraemer|first4=K.H.|last5=Lehmann|first5=A.R.|last6=Gearhart|first6=P.J.|year=2001|title=DNA polymerase-eta is an A-T mutator in somatic hypermutation of immunoglobulin variable genes|journal=Nat. Immunol.|volume=2|issue=6|pages=537–541|DOI=10.1038/88740|PMID=11376341}}</ref><ref name=":8">{{Cite journal|last=Wilson|first=T.M.|last2=Vaisman|first2=A|last3=Martomo|first3=S.A.|last4=Sullivan|first4=P|last5=Lan|first5=L.|last6=Hanaoka|first6=F.|last7=Yasui|first7=A.|last8=Woodgate|first8=R.|last9=Gearhart|first9=P.J.|year=2005|title=MSH2-MSH6 stimulates DNA polymerase eta, suggesting a role for A:T mutations in antibody genes|journal=J. Exp. Med.|volume=201|issue=4|pages=637–645|DOI=10.1084/jem.20042066|PMID=15710654|PMC=2213055}}</ref><ref name=":9">{{Cite journal|last=Delbos|first=F|last2=Aoufouchi|first2=S|last3=Faili|first3=A|last4=Weill|first4=J-C|last5=Reynaud|first5=C-A|year=2007|title=DNA polymerase-eta is the sole contributor of A/T modifications during immunoglobulin gene hypermutation in the mouse.|journal=J. Exp. Med.|volume=204|issue=2007|pages=17–23|DOI=10.1084/jem.20062131|PMID=17190840|PMC=2118439}}</ref>
This error-prone DNA polymerase is the only known error-prone polymerase involved in SHM in vivo.
What is often ignored in these studies is that this Y family DNA polymerase enzyme is also an efficient reverse transcriptase as demonstrated in ''in vitro'' assays.<ref name=":12">{{Cite journal|last=Franklin|first=A.|last2=Milburn|first2=P. J.|last3=Blanden|first3=R.V.|last4=Steele|first4=E. J.|date=2004|title=Human DNA polymerase-eta an A-T mutator in somatic hypermutation of rearranged immunoglobulin genes, is a reverse transcriptase|journal=Immunol. Cell Biol.|volume=82|issue=2|pages=219–225|DOI=10.1046/j.0818-9641.2004.01221.x|PMID=15061777}}
=== 逆転写酵素モデル ===
[[ファイル:Adenosine_chemical_structure.jpg|サムネイル|94x94ピクセル|[[アデノシン]]]]
[[ファイル:Inosine_chemical_structure.jpg|サムネイル|90x90ピクセル|[[イノシン]]]]
The more controversial competing mechanism is an RNA/RT-based mechanism (reverse transcriptase model of SHM) which attempts to explain the production of the full spectrum of strand-biased mutations at A:T and G:C base pairs whereby mutations of A are observed to exceed mutations of T (A>>>T) and mutations of G are observed to exceed mutations of C (G>>>C). This involves error-prone cDNA synthesis via an RNA-dependent DNA polymerase copying the base modified Ig pre-mRNA template and integrating the now error-filled cDNA copy back into the normal chromosomal site. The errors in the Ig pre-mRNA are a combination of adenosine-to-inosine (A-to-I) RNA editing<ref name=":10">{{Cite journal|last=Steele|first=E.J.|last2=Lindley|first2=R.A.|last3=Wen|first3=J|last4=Weiler|first4=G.F.|year=2006|title=Computational analyses show A-to-G mutations correlate with nascent mRNA hairpins at somatic hypermutation hotspots.|journal=DNA Repair|volume=5|issue=11|pages=1346–1363|DOI=10.1016/j.dnarep.2006.06.002|PMID=16884961}}
The evidence for and against each mechanism is critically evaluated in Steele<ref name=":0">{{Cite journal|last=Steele|first=E.J.|year=2016|title=Somatic hypermutation in immunity and cancer: Critical analysis of strand-biased and codon-context mutation signatures.|journal=DNA Repair|volume=45|pages=1–24|DOI=10.1016/j.dnarep.2016.07.001|PMID=27449479}}
Recently Zheng et al.<ref name=":15">{{Cite journal|last=Zheng|first=Yuxuan|last2=Lorenzo|first2=Claire|last3=Beal|first3=Peter A.|date=27 January 2017|title=DNA editing in DNA/RNA hybrids by adenosine deaminases that act on RNA|journal=Nucleic Acids Research|volume=45|issue=6|pages=3369–337|DOI=10.1093/nar/gkx050|PMID=28132026|PMC=5389660}}</ref> have supplied critical independent validation by showing that Adenosine Deaminase enzymes acting on RNA (ADARs) can A-to-I edit both the RNA and DNA moieties of RNA:DNA hybrids in biochemical assays in vitro. RNA:DNA hybrids of about 11 nucleotides in length are transient structures formed at transcription bubbles in vivo during RNA polymerase II elongation.
A preliminary analysis of the implications of the Zheng et al. data has been submitted as formal paper to a refereed journal by Steele and Lindley.<ref name=":17">{{Cite journal|last=Steele|first=E.J.|last2=Lindley|first2=R.A.|year=2017|title=RNA DNA Hybrids and SHM|url=https://www.academia.edu/32522661|journal=DNA Repair|volume=April 15, 2017|pages=1–6|DOI=10.1016/j.dnarep.2017.04.004|PMID=28482199}}</ref> The Zheng et al.<ref name=":15">{{Cite journal|last=Zheng|first=Yuxuan|last2=Lorenzo|first2=Claire|last3=Beal|first3=Peter A.|date=27 January 2017|title=DNA editing in DNA/RNA hybrids by adenosine deaminases that act on RNA|journal=Nucleic Acids Research|volume=45|issue=6|pages=3369–337|DOI=10.1093/nar/gkx050|PMID=28132026|PMC=5389660}}
In this regard Robyn Lindley has also recently discovered that the Ig-SHM-like strand-biased mutations in cancer genome protein-coding genes are also in "codon-context". Lindley has termed this process targeted somatic mutation (TSM) to highlight that somatic mutations are far more targeted than previously thought in somatic tissues associated with disease.<ref name=":5">{{Cite journal|last=Lindley|first=R.A.|year=2013|title=The importance of codon context for understanding the Ig-like somatic hypermutation strand-biased patterns in TP53 mutations in breast cancer.|journal=Cancer Genet.|volume=206|issue=6|pages=222–226|DOI=10.1016/j.cancergen.2013.05.016|PMID=23880211}}</ref><ref name=":6">{{Cite journal|last=Lindley|first=R.A.|last2=Humbert|first2=P|last3=Larmer|first3=C|last4=Akmeemana|first4=E.H.|last5=Pendlebury|first5=C.R.R.|year=2016|title=Association between Targeted Somatic Mutation (TSM) signatures and HGS-OvCa progression|journal=Cancer Med.|volume=5|issue=9|pages=2629–2640|DOI=10.1002/cam4.825|PMID=27485054|PMC=5055158}}</ref>
The TSM process implies an "in-frame DNA reader" whereby DNA and RNA deaminases at transcribed regions are guided in their mutagenic action, by the codon reading frame of the DNA.
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== 関連項目 ==
* {{仮リンク|親和性成熟|en|Affinity maturation}}
* {{仮リンク|クローンアネルギー|en|Clonal Anergy}}
* [[免疫系]]
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* {{MeSH name|Immunoglobulin+somatic+hypermutation}}
{{DEFAULTSORT:たいさいほうちようへんい}}
[[Category:免疫系]]
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