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JP3585238B2 - 真核細胞における部位特異的突然変異誘発のための化合物および方法 - Google Patents

真核細胞における部位特異的突然変異誘発のための化合物および方法 Download PDF

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JP3585238B2
JP3585238B2 JP51636795A JP51636795A JP3585238B2 JP 3585238 B2 JP3585238 B2 JP 3585238B2 JP 51636795 A JP51636795 A JP 51636795A JP 51636795 A JP51636795 A JP 51636795A JP 3585238 B2 JP3585238 B2 JP 3585238B2
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Description

1. 発明の分野
本発明は、分子遺伝学の分野に関するものである。特に、本発明は、生存している培養真核細胞に特定の遺伝的変異を導入するための核酸化合物ならびにその使用方法に関する。より詳細には、本発明は、二本鎖核酸の１本の鎖の一部が2'−Ｏまたは2'−OMeリボースを含むヌクレオチドからなり、残りの部分がデオキシリボースヌクレオチドからなる、実質的にワトソン・クリック型塩基対を形成した二本鎖核酸に関する。
2.発明の背景
2.1. キメラおよび／またはハイブリッド二本鎖核酸
本発明の分野は核酸に関するものである。核酸はヘテロポリマー、すなわち、配向されたホスホジエステル結合またはその誘導体によってポリマーへと連結されている、同一でないサブユニットのポリマーである。二本鎖核酸とは、ウラシルまたはチミンに対してはアデニン、シトシンに対してはグアニンという塩基対の法則に従って、二本鎖の第一鎖の各塩基が二本鎖の第二鎖の塩基に対応している核酸のことである。こうした対応（correspondence）を有する逆平行二本鎖はワトソン・クリック型対合（Watson−Crick pairing）をしていると言われる。二本鎖核酸には主に２つのタイプがあり、リボ核酸とデオキシリボ核酸である。それぞれのリボヌクレオチドには同様のデオキシリボヌクレオチドがあり、例えば、アデノシンとデオキシアデノシン、シチジンとデオキシシチジン、グアノシンとデオキシグアノシン、ウリジンとチミジンである。この分野において、リボヌクレオチドとデオキシリボヌクレオチドの両方が同一の鎖に存在している核酸は混合またはキメラ（以後「キメラ」と言う）核酸と称される。デオキシリボヌクレオチドとリボヌクレオチドが互いに対応している二本鎖核酸はハイブリッド二本鎖と呼ばれる。２本の鎖がそれらの塩基の一部において二本鎖核酸の領域を形成している場合、生ずる分子はヘテロ二本鎖と称される。
たいていの場合、二本鎖核酸の２本の鎖は共有結合しておらず、ワトソン・クリック型対合によってのみ結びついている。しかしながら、二本鎖の２本の鎖をオリゴヌクレオチドにより連結させて一本鎖ポリマーを形成することができる。リンキングオリゴヌクレオチドはワトソン・クリック型塩基対を形成しない。第一鎖と第二鎖が一本鎖ポリマーの一部であるヘテロ二本鎖は「ヘアピン二本鎖」または「ステム・ループ（stem and loop）」構造と呼ばれる。以後、前者の用語を用いることにする。
ここで用いるキメリズム（chimerism）は核酸ポリマーの特性であり、そしてハイブリディズム（hybridism）は二本鎖の特性である。例えば、mRNAとその鋳型はどちらもキメラではないがハイブリッド二本鎖を形成し、一方、例えば、キメラオクタヌクレオチド5'd（TTTT）−ｒ（CCCC）3'および5'r（GGGG）−ｄ（AAAA）3'は互いとワトソン・クリック型二本鎖を形成するであろうが、得られる二本鎖はハイブリッド二本鎖ではない。ハイブリッド二本鎖ではない二本鎖核酸を以後「ホモ二本鎖」と呼ぶことにする。特にことわらないかぎり、ホモ二本鎖核酸はデオキシヌクレオチド含有二本鎖のことである。なお、当業者はワトソン・クリック型二本鎖の形成を「ハイブリダイゼーション（ハイブリッド形成）」と呼んでいるが、その場合でさえハイブリッド二本鎖核酸は存在しないことに注意されたい。
Ｘ線回折および二次元NMRによるキメラおよび／またはハイブリッド二本鎖核酸の構造の研究に関心のある人達は、彼らの研究に使用するためのキメラ核酸およびハイブリッド二本鎖核酸を合成してきた。例えば、Salazar,M.ら,1994,J.Mol.Biol.241:440−55およびEgli,M.ら,1993,Biochemistry 32:3221−37（r3d7・d10型のキメラハイブリッド二本鎖）;Ban,C.ら,1994,J.Mol.Biol.236;275−85（d5r1d4型の自己相補的キメラハイブリッド二本鎖）;Chou,S.H.,1991,Biochemistry 30:5248−57（d4r4d4型の自己相補および非自己相補キメラハイブリッド二本鎖）を参照のこと。これらの二本鎖核酸の相補鎖は互いに共有結合で結びついているのではなく、ワトソン・クリック型対合によってのみ結びついていた。
キメラ核酸を合成した第二グループの科学者達は、リボザイム、すなわち自己開裂性であるかまたは他のRNAを開裂するRNA分子、の研究および使用に関心のある人達であった。Perreault,J.P.ら,1990,Nature 344:565;Taylor,N.R.ら,1992,Nucleic Acids Research 20:4559−65;Shimaya T.,1993,Nucleic Acids Research 21:2605を参照のこと。これらの研究者らは、キメラリボザイムが活性であって、しかもRNAリボザイムよりもヌクレアーゼ消化に対して抵抗することを見いだした。キメラリボザイムは自己相補的であり、つまり、ワトソン・クリック型対合鎖が共有結合で結びついている。キメラリボザイムの研究に際して合成された化合物は、キメラリボザイムが安定したハイブリッド二本鎖を含まないという点で、構造研究のために合成され使用された上記のハイブリッド二本鎖分子とは相違している。こうして、DNA結合アームを有するキメラリボザイムがその基質に結合してハイブリッド二本鎖を形成する。Yang,J.H.ら.1990,Biochemistry 29:11156−60を参照のこと。また、Sawata,S.ら,1993,Nucleic Acids Research 21:5656−60;Hendry,P.ら,1992,Nucleic Acids Research 20:5737−41;Shimayama,T.ら,1993,Nucleic Acids Research 21:2605も参照のこと。リボザイムはRNA基質の開裂を触媒し、それゆえハイブリッド二本鎖が溶解される。
2.2. 真核細胞における部位特異的遺伝的変異
分子生物学の分野に習熟した人達は、多くの場合に、単に新しいポリ核酸配列（すなわち、新しい遺伝子）を標的真核細胞の中に導入するのではなく、むしろ標的細胞中の特定の既存遺伝子を改変することが望まれていることを認識している。標的細胞は培養下で用いたり、またはトランスジェニック動物を作出するために用いることができる。
培養下の真核細胞にDNAを導入するための様々な技法が開発されている。こうした技法として、リン酸カルシウム沈殿およびDEAE−デキストラン媒介エンドサイトーシス、エレクトロポレーション、リポソーム媒介融合、そして複製能のないウイルスによる形質導入が挙げられる。しかし、このような技法は真核細胞に機能性遺伝子を導入することはできても、特定の既存遺伝子に変化（突然変異）を簡単に導入することはできない。導入後、外因性DNAは、相同的組換えにより特定位置にではなく、非正統的組換え（illegitimate recombination）により細胞ゲノムの不特定位置に隔離される。
現在まで、高等真核細胞、すなわち哺乳動物細胞またはトリ細胞に、特定部位のまたは部位特異的な遺伝的変異（突然変異誘発）を導入するための一般的に満足のゆく方法は存在していない。高等真核細胞においては非常に長い（＞1kb）核酸の導入による相同的組換えが可能であるが、これらの技法には入念な選択技術の使用が必要となる。なんとなれば、高等真核細胞における非正統的組換え率は相同的組換え率を上回るからである。Thomas,K.R.＆ Capecchi,M.R.,1987,Cell 52:503を参照のこと。さらに、Valancius,V.＆ Smithies O.,1991,Mol.Cell.Biol.11:4389（真核細胞における線状化プラスミドとスーパーコイルドプラスミドの相同的組換えの比較）を参照のこと。
部位特異的突然変異誘発を達成するための一つのアプローチは、細胞の中に直接一本鎖オリゴデオキシヌクレオチドを導入することであった。この手法は酵母Saccharomyces cerevisiaeにおいて成功裏に採用され、酵母では相同的組換えが高等真核細胞中よりも著しく活発に起こった。Moerschell,R.P.ら,1988,Proc.Natl.Acad.Sci.85:524−28;Yamamoto,T.ら,1992,Yeast 8:935−48を参照のこと。しかし、今日まで、一本鎖オリゴヌクレオチドを用いた哺乳動物細胞またはトリ細胞の形質転換が成功したという報告は皆無である。
標的DNAの構造と哺乳動物における相同的組換え率との関係は、交互のプリンおよびピリミジン塩基の領域、すなわち［ｄ（TG）30・ｄ（AC）30］が組換え率を表すということを示した研究によって推論し得る。これらの成果は培養哺乳動物細胞中の非複製プラスミドの研究において実証された。Wahls,W.P.ら,1990,Mol.Cell.Biol.10:785−93を参照のこと。こうした実験が外因性核酸と細胞ゲノムとの組換えを明らかにするまで拡張されることはなかった。
大腸菌において相同的組換えを促進するタンパク質RecAを用いて真核細胞での相同的組換えを促進させようとする試みがなされた。しかし、こうした試みは明らかに成功しなかった。例えば、W.Bertlingの米国特許第4,950,599号には、真核細胞中でRecAを用いても部位特異的突然変異率が極端に低いこと、そして相同的組換え率が向上しないことが記載されている。D.Zarling ＆ E.Senaの特許公開WO 93/22443およびD.C.Gruenert ＆ K.Kunzelmannの公開WO 94/04032は両方とも嚢胞性繊維症に関係した培養細胞系の遺伝的欠陥を修正することを記述している。これらの刊行物は主として操作方法に関するデータよりもむしろ原理を照明する実験データを載せている。こうして、核に接近させてポリヌクレオチド/RecA複合体を導入するために、ZarlingおよびGruenertは膜透過性にした細胞を利用しているが、こうした細胞は増殖能を持ち合わせていない。さらに、RecAにより促進された相同的組換えが無傷の細胞において起こったと主張する場合でさえ、これらの刊行物はその頻度の定量的概算値をまったく提示していない。かくして、原核生物RecAの使用は、生存真核細胞における相同的組換え率が相同的組換えの自然発生率よりも顕著に高いことを納得できる程度に明示していない。
3. 発明の概要
本発明は、デオキシリボヌクレオチドとリボヌクレオチドの両方を含み、対象の遺伝子と相同性の、単一の、共有結合で結びついた二本鎖オリゴヌクレオチドに関する。遺伝的変異を生み出すために、相同領域内に１個またはそれ以上の非対応（以後「異種」または「ミューテーター」と言う）塩基対が存在する。相同的組換えの正常な構成的細胞過程は標的ゲノム部位にミューテーターヌクレオチドを挿入させる。本発明の二本鎖オリゴヌクレオチド（以後「キメラベクター」と言う）は、対象となる遺伝子に異種塩基対を導入することによって該遺伝子を特異的に改変するために用いることができる。異種塩基対は対象の遺伝子と異なる塩基対、または対象の遺伝子に存在するものに加えた塩基対（挿入）であり得、また、異種塩基対は対象の遺伝子中に存在する塩基対の非存在（欠失）であり得る。本発明は、幾分かは、ベクター中に約15〜50塩基対のハイブリッド二本鎖核酸の領域を含めると、対象遺伝子の変異率が非常に増加するという知見に基づいている。異種塩基対の領域が１〜50塩基対である場合、異種塩基対は本発明のベクター中にホモ二本鎖かハイブリッド二本鎖のどちらかとして存在し得る。異種塩基対が50塩基対より長い場合、それらはホモ二本鎖として存在することが好適である。
ベクターは、真核細胞への核酸の導入を可能にする任意の公知方法によって標的細胞の中に導入することができる。理論によって拘束されないが、キメラベクターは、標的細胞の組換え／修復機構によって取り込まれ、遺伝子変換または相同的組換えにより標的遺伝子を変化させると考えられる。
【図面の簡単な説明】
図１は、２つのキメラベクターの模式図を示す。符号の説明は次のとおりである。1:第一鎖、2:第二鎖、3:異種領域、4:相同領域、5:リンカー、6:連結部位。
Figure 0003585238
図1Aは、Ｒ−Ｄ−Ｒ型の連結されたキメラベクターである。
図1Bは、単一の3'および5'末端をもつＲ−Ｄ−Ｒ型のヘアピンキメラベクターである。
5. 発明の詳細な説明
5.1. 本発明のキメラベクターの説明
本発明は、デオキシリボース含有塩基とリボース含有塩基の両方を含む二本鎖核酸を意図している。それらはDNAとRNAの両領域を含み、それゆえ「キメラベクター」と称される。キメラベクターのリボヌクレオチドの2'−Ｏはメチル化され得る。また、ホスホジエステルはどれもホスホロチオジエステルまたはメチホスホノジエステルで置換することができる。
本発明のキメラベクターは単一の核酸ポリマーである。従って、本発明のキメラベクターはワトソン・クリック型塩基対を形成していない少なくとも１塩基、通常は３または４塩基、の少なくとも１つの領域を含まねばならない。これらの不対領域はワトソン・クリック型塩基対の２本の鎖の間のリンカーとして利用される。不対ヌクレオチド領域を有する合成された他のキメラヌクレオチドと対照的に、キメラベクターは酵素活性がない。すなわち、それらは化学反応を触媒しないか、または、それら自体がATPのような生物学的エネルギー源の非存在下で化学反応を受ける。
好ましい実施態様では、リンカーの塩基はデオキシリボヌクレオチドである。ポリマーの3'および5'末端が相補鎖の隣接ヌクレオチドにワトソン・クリック型塩基対合されるように、２つのリンカーをもつキメラベクターを構築することができる。その後、それらは、キメラベクターが単一の連続した環状核酸ポリマーを形成するように連結させることができる。
キメラベクターの残っている実質的に全部の塩基はワトソン・クリック型塩基対を形成する。ここで用いる「塩基がワトソン・クリック型対合する」または「それらが二本鎖核酸を形成する」という記述は、適当な温度および塩条件下でそれらが塩基対または二本鎖核酸を形成しうることを意味すると理解すべきである。いくつかの低塩および／または高温条件下では、ワトソン・クリック型塩基対が熱力学的に安定であることをやめて、二本鎖核酸が融解または変性を起こしうると理解すべきである。また、１個または２個の塩基対ミスマッチは本発明の操作可能性に影響を及ぼさないことを認識すべきである。
本発明キメラベクターは、標的遺伝子に変化（突然変異）を特異的に導入することを目的としたものである。変換の遺伝子部位は、標的部位の配列と同じ（相同である）配列（以後、相同領域と言う）をもつようにキメラベクターの一部を選択することによって決定される。キメラベクター配列と標的遺伝子の間で異なる領域は異種領域と称される。キメラベクターは標的遺伝子に対して異種であるが、ベクターのこの領域においてヘテロ二本鎖でないことに注意されたい。本発明の好ましい実施態様によれば、各キメラベクターには介在異種領域に隣接する２つの相同領域が存在し、これら３つの領域はすべて単一の連続した二本鎖核酸中に存在する。さらに、本発明によれば、各相同領域はハイブリッド二本鎖核酸の部分を含んでいる。ハイブリッド二本鎖の部分は少なくとも４塩基対、好ましくは８塩基対、より好ましくは約20〜30塩基対でありうる。キメラベクターの機能は、3'および5'末端の互いへの連結を可能にするように配置された、ハイブリッド二本鎖の領域内のホモ二本鎖のジヌクレオチド塩基対によって影響されることはない。２つの相同領域の合計の鎖長は少なくとも20塩基対、好ましくは40〜60塩基対でありうる。
本発明によると、ホモ二本鎖核酸の領域はベクターのハイブリッド二本鎖／相同領域の間に配置することができる。介在するホモ二本鎖は異種領域を含むことができる。異種領域が約50塩基対以下、好ましくは約20塩基対以下である場合には、ホモ二本鎖領域の介在は任意である。異種領域が約20塩基対を越える場合は、異種領域を含むホモ二本鎖を介在させることが好適である。
5.2. 本発明のキメラベクターの構築
本発明のキメラベクターは任意の方法で合成することができる。キメラベクターの最も簡便な合成法は、固相DNA合成で用いる技法の変法によるものである。Caruthers,M.H.,1985,Science 230:281−85;Itakura,K.ら,1984,Ann.Rev/Biochem.53:523−56を参照のこと。RNAおよびキメラ核酸の合成を可能にする変法は、Scaringe,S.A.ら,1990,Nucleic Acids Research 18:5433−41;Usman,N.ら,1992,Nucleic Acids Research 20:6695−99;およびSwiderski,P.M.ら,1994,Anal.Biochem 216:83−88に記述されており、これらの全体を参考としてここに組み入れるものとする。キメラ核酸の合成に関する最近の進展は、Usman,N.＆ Cedergren,R.,1992,Trends Bioch.Sci.17:334−９に概説されている。
２つのハイブリッド二本鎖領域間にホモ二本鎖領域が介在したキメラベクターは半合成法を使って構築することができる。ヘアピンコンホメーションを有する２つの合成キメラポリ核酸を構築すべきである。２つの異なる制限酵素消化産物のオーバーラップに相補的なオーバーラップ付着末端をもつ、２つのキメラ核酸の遊離5'および3'末端を構築する。相補的な制限酵素消化末端をもつホモ二本鎖領域を用意する。クローン化DNA断片の両末端への制限酵素部位の付加は当業者によく理解された技法を用いて行うことができ、例えば、限定するものではないが、伸長プライマーを用いるPCR増幅または制限部位を含むリンカーの平滑末端連結がある。２つのキメラヌクレオチドとホモ二本鎖領域は通常の酵素法により連結させることができる。キメラオリゴヌクレオチドが両末端で連結された産物は、非変性条件下でTrisホウ酸EDTA緩衝液にて６％ポリアクリルアミドゲル中で電気泳動を行うことにより、不完全に反応した基質から分離することができる。線状のキャップされた分子は拘束されて、これらの条件下ではより遅く泳動する。
本発明においては自然界に存在するヌクレオチドのみを含むキメラベクターを使用することができる。約20リボヌクレオチドのハイブリッド二本鎖領域を含むキメラベクターは、in vitroでRNase Hに耐性であることが判明した。酵素分解に対する耐性は、リボヌクレオチドを2'−Ｏメチル化リボヌクレオチドで置換することによっても得られる。加えてまたは別途、核酸のホスホジエステル結合をホスホロチオジエステルで置換してもよい。Shimayama,T.ら,1993,Nucleic Acids Research 21:2605を参照のこと。アラビノース含有ヌクレオチドも使用できる。ここで用いる「核酸」という用語は、こうした修飾核酸を包含するものである。
5.3. 本発明のキメラベクターの使用
本発明のキメラベクターは、標的細胞のゲノムの特定位置に突然変異を起こさせるために使用される。標的細胞のゲノムの特定位置はその核酸配列（以後、標的配列と言う）によって定められる。本発明によると、ハイブリッド二本鎖のいくつかの領域の存在を別にすれば、相同領域が標的配列と同一であるキメラベクターが構築される。導入しようとする変化は異種領域によってコードされる。この変化は該配列の１個以上の塩基の変化または１個以上の塩基の付加でありうる。標的配列の変化が約20個以下の塩基の付加である場合、本発明はハイブリッド二本鎖の１つまたは２つの領域を使って実施できる。標的配列の変化が約50個以上の塩基の付加である場合は、異種領域をホモ二本鎖領域内に含ませることが好ましい。
本発明を実施するには、キメラベクターを標的細胞の核の中に導入することが必要である。こうした導入を起こさせる方法はどれも使用できる。かかる方法として、エレクトロポレーション、DEAE−デキストラン、リン酸カルシウム沈殿、リポソーム媒介融合（リポフェクション）、そして直接注入が挙げられる。エレクトロポレーションが特に適している。
本発明の一実施態様において、キメラベクターはトランスジェニック動物を作出するために用いられる。Brinster,R.L.ら,1989,Proc.Natl.Acad.Sci.86:7087に記載の方法に従って、卵の前核にキメラベクターを導入することができる。さらに、T.E.WagnerおよびP.C.Hoppeの米国特許第4,873,191号を参照のこと。上記文献の内容をそのままここに参考として組み入れるものとする。別法として、キメラベクターを胚性幹細胞に導入し、その胚性幹細胞と正常な芽細胞との凝集によってもキメラ動物を作ることができる。トランスジェニック動物は、Capecchi,M.R.,1989,Science 244:1288（その全体を参考としてここに組み入れる）に記載の方法に従って、キメラ動物の子孫として得ることができる。
エレクトロポレーションを用いると、10,000個の処理細胞につき１個程度の細胞が標的配列で特異的に突然変異を起こす（以後「形質転換された」と言う）。かくして、本発明の実施には、突然変異を起こしていない大多数の細胞の中から形質転換された細胞を選別する方法の使用が含まれる。一実施態様において、細胞の形質転換は生育に有利な性質を付与する。生育に有利な性質の非限定的な例として、薬剤耐性、生育調節の変更および代謝産物利用能の変更が挙げられる。別の実施態様では、選別方法としてネガティブ選別を用いる。この方法では、形質転換された細胞が選別条件下で増殖できなくなり、一方、非形質転換細胞は増殖中の細胞を選択的に破壊する条件にさらすことにより除かれる。
また、形質転換細胞は免疫蛍光で検出しうる細胞表面抗原の改変された表現型をもつことができ、この場合は蛍光活性化セルソーター（Fluorescence Activated Cell Sorter）を使って選別することができる。
トランスジェニック動物を前核注入により作出する場合のように、細胞の中にキメラベクターを導入する方法が直接注入である場合は、形質転換率が細胞10,000個につき１個より多くなる。その結果、選別の必要性がかなり軽減される。
一般に、キメラベクターの有効量はエレクトロポレーションで形質転換しようとする培養細胞100万個あたりキメラベクター10〜1000ngの範囲である。
6. 実施例
6.1. 実施例1:Ustilago菌におけるin vivo活性
野生型のUstilagoは機能性ura−３遺伝子（その産物はウラシル生合成経路の一部をなす）をもっている。野生型Ustilagoを5'−fluororotic acid（5FOA）培地で生育させると、細胞はウラシル生合成経路へのこの酸の取込みのために死滅する。ura−３遺伝子に突然変異が起こってura−3 mRNAが産生されなくなると、5FOA培地上でも細胞は生き残る。
内因性ura−３遺伝子の配列は当技術分野で知られている。一組の実験において、この配列の塩基358をチミジンからアデニンに変えた。この変異は機能不全タンパク質をもたらす。
キメラベクターを次のように合成した：
塩基358で突然変異を起こさせるためのベクター（358 RNAベクター）：
Figure 0003585238
358ベクターはヘアピンコンホメーションをとる。下線部分の塩基はリボ核酸残基を示す。太字はミューテーター（異種領域）を示す。イタリック体で記した「Ｔ」は不対合塩基を示す。
対照として使用するために、同一の配列をもつがリボ核酸を含まないベクターも構築した。このベクターではウラシルの代わりにチミジンが用いられた。
塩基358で突然変異を起こさせるための対照ベクター（DNA 358ベクター）
Figure 0003585238
このベクターもヘアピンコンホメーションをとる。この場合も太字の残基がミューテーターである。
in vivo形質転換実験を行うにあたり、当技術分野で公知の方法に従ってU.maydis細胞（107個）から50μｌ形質転換緩衝液中106個の回収率でプロトプラストを作り、異なる量のキメラベクターまたは均質（DNAのみ）ベクターをプロトプラストと37℃で混合してトランスフェクトした。次に細胞を選択培地にまき、生存コロニー（形質転換体）の数を数えた。結果を以下の表に示す。
Figure 0003585238
これらのデータは、RNA358ベクターによる細胞のトランスフェクションが対応するDNAベクターを用いたトランスフェクションよりも大幅に細胞の生存を高めることを示している。
6.2. NIH 3T3細胞の形質転換
NIH 3T3細胞は良性の（制御できる）増殖特性を有するヒト細胞である。悪性の（制御できない）増殖特性は、Gly12をThrで置き換えるがん遺伝子Ｈ−rasの単一の点突然変異によって付与される。かくして、突然変異Ｇ→T12は容易に選択可能な増殖特性の変化を生じさせる。Taparowsky,E.ら,1982,Nature 300:762;Sukumar S.ら,1983,Nature 306:658を参照のこと。
Ｇ→T12突然変異を誘導するために、次の配列を有するキメラベクターを構築した：
Figure 0003585238
この配列は通常の一文字表記で表してある。更なる特徴として、RNAには下線が引いてあり、不対合塩基はイタリック体で、そしてミューテーター塩基は太字で示してある。環化後、キメラベクターは２つのトリチミジニル配列によって実質的に相補的な２つの鎖に分割され、そしてリボース含有ヌクレオチドはすべてこれら２つの鎖の一方にのみ存在することに注目されたい。
2'−OMeリボース塩基を用いて、４個のデオキシリボース残基に隣接する１つ（Ｒ）および２つ（Ｒ−Ｄ−Ｒ）のハイブリッド二本鎖領域をそれぞれ有する２つの型のキメラベクターを合成した。Ｒ−Ｄ−Ｒ型は上記の配列番号３に示され、Ｒ型は塩基６−９（CGAC）がデオキシヌクレオチドであったこと以外は同一である。5'および3'末端はデオキシヌクレオチドであることに注目されたい。組換えDNA法で用いるものと同じDNAリガーゼ法を用いて合成後のキメラベクターを環化させた。連結後、環化したキメラベクターをD600ゲル（AT Biochem,Malvern,PA）中での分離用電気泳動を２回繰り返すことにより基質から単離した。
対照のベクターは次のものであった:1）ハイブリッド二本鎖を欠いている同一の配列（データを示した、「ホモ二本鎖」）;2）配列5'−GCCCACACCGACGGCGCCACCAC−3'（配列番号４）を有する不対合DNA（データを示した、「sDNA」）;3）異種領域を含まない、それゆえミューテーターヌクレオチドを含まないキメラベクター（データを示さず）。
この実験はエレクトロポレーション法を使ってNIH 3T3細胞（１×106個）を形質転換することにより実施した。エレクトロポレーション後、細胞を４×103個/cm2の密度でまき、14日間培養した。フォーカス形成細胞をクリスタルバイオレットで染色して形質転換体を視覚化した。陽性対照として、H rasのT12型をコードするプラスミドpT24を用いた。この対照を用いて、トランスフェクトされたNIH 3T3細胞中における非正統的組換えレベルを測定した。実験を５回繰り返し、その結果を以下の表に要約して示す。以下に示した結果に加えて、ミューテーターコドンを含まないキメラベクターを使用した対照実験では、NIH 3T3細胞の形質転換フォーカスが全く現れなかった。
Figure 0003585238
これらの結果から、キメラベクターは相同的組換えにより特定の突然変異を導入して哺乳動物細胞を形質転換したことがわかる。この実験での形質転換率は、全突然変異Ｈ−ras遺伝子を含むpT24陽性対照ベクターを用いたトランスフェクションにおいて観察された非正統的組換えによる形質転換率よりも高かった。かくして、キメラベクターを用いることにより、非正統的組換え率よりも高い、哺乳動物細胞での相同的組換え率が達成されたことになる。
配列表
配列番号:1
配列の長さ:37塩基対
配列の型：核酸
鎖の数：自己相補的（self complementary）
トポロジー：直鎖状
配列の種類:DNA/RNA
配列の特徴：
特徴を表す記号：−
存在位置:19..32
他の情報:/ラベル＝ａ
／注＝“RNA"
配列
Figure 0003585238
配列番号:2
配列の長さ:37塩基対
配列の型：核酸
鎖の数：自己相補的
トポロジー：直鎖状
配列の種類:DNA
配列
Figure 0003585238
配列番号:3
配列の長さ:53塩基対
配列の型：核酸
鎖の数：自己相補的
トポロジー：直鎖状
配列の種類:DNA/RNA
配列の特徴：
特徴を表す記号：−
存在位置:2..5
他の情報:/ラベル＝ｂ
／注＝“RNA"
配列の特徴：
特徴を表す記号：−
存在位置:10..21
他の情報:/ラベル＝ｄ
／注＝“RNA"
配列の特徴：
特徴を表す記号：−
存在位置:51..52
他の情報:/ラベル＝ｆ
／注＝“RNA"
配列
Figure 0003585238
配列番号:4
配列の長さ:23塩基対
配列の型：核酸
鎖の数：自己相補的
トポロジー：直鎖状
配列の種類:DNA
配列
Figure 0003585238

Claims (4)

  1. 多くても１つの3'末端と１つの5'末端をもつキメラ核酸であって、
    a.不対領域が前記の核酸を第一鎖と第二鎖に分離するように配置されている、連続した不対塩基の領域；
    b.第一鎖の塩基が第二鎖の塩基に対応している、鎖長が少なくとも15塩基対のワトソン・クリック型塩基対を形成した核酸の領域；
    を含んでなり、その際、
    （ｉ）第一鎖は2'−Ｏまたは2'−OMeリボースで構成された連続した少なくとも３ヌクレオチドの領域を含み、これらのヌクレオチドがハイブリッド二本鎖としてワトソン・クリック型塩基対を形成しており、
    （ii）ワトソン・クリック型塩基対を形成した核酸の領 域は、標的遺伝子配列に相同な２つの領域を含み、これ ら２つの相同領域がハイブリッド二本鎖の部分を含み、 これらの相同領域の間には標的遺伝子配列に変異を引き 起こす配列を含む異種領域が介在している、
    ことを特徴とするキメラ核酸。
  2. 第一鎖が２つのハイブリッド二本鎖領域を形成する2'−Ｏまたは2'−OMeリボースで構成された連続ヌクレオチドの２つの領域を含み、各ハイブリッド二本鎖領域は少なくとも４塩基対の長さであり、そして少なくとも１塩基対のホモ二本鎖の介在領域が２つのハイブリッド二本鎖領域間に配置されており、前記のホモ二 本鎖の介在領域が異種領域を含む、請求項１に記載のキメラ核酸。
  3. 核をもつ細胞または細胞集団のゲノムの標的配列に所定の変異を導入する方法であって、
    a.標的配列に相同な２つの領域と、それらの間に配置された、前記の変異をコードする異種領域と、を含む請求項１または２に記載のキメラ核酸を用意し、
    b.該キメラ核酸を該細胞の核内に維持して、該キメラ核 酸と前記の標的配列が遺伝的組換えを起こすようにする、
    ことを含んでなる方法。
  4. 非ヒトトランスジェニック動物の作製に用いるための、請求項１または２に記載のキメラ核酸。
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EP0733059A4 (en) 1997-05-21
DE733059T1 (de) 1997-08-28
DE69425903D1 (de) 2000-10-19
GR3034988T3 (en) 2001-03-30
KR960706500A (ko) 1996-12-09
WO1995015972A1 (en) 1995-06-15
KR100386337B1 (ko) 2004-03-24
JPH09506511A (ja) 1997-06-30
US5871984A (en) 1999-02-16
DK0733059T3 (da) 2000-10-16
ATE196311T1 (de) 2000-09-15
EP0733059B1 (en) 2000-09-13
CN1117866C (zh) 2003-08-13
CN1048254C (zh) 2000-01-12
ES2149962T3 (es) 2000-11-16
US5565350A (en) 1996-10-15
US5756325A (en) 1998-05-26
AU691550B2 (en) 1998-05-21
CA2178729A1 (en) 1995-06-15
PT733059E (pt) 2001-03-30
EP0733059A1 (en) 1996-09-25
AU1399595A (en) 1995-06-27
NZ278490A (en) 1998-03-25
CN1215755A (zh) 1999-05-05

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