User:Kaguya-Taketori/RNA

mRNA的球棍模型,其中灰色小球代表碳原子,紅色小球代表氧原子,藍色小球代表氮原子,橘色小球代表磷原子
圖爲mRNA前體上的一段莖環結構。含氮鹼基以綠色表示,而磷酸-核糖骨架則以藍色表示。注意莖(雙鏈)結構是由一條RNA單鏈通過摺疊形成

核糖核酸(英語:Ribonucleic acid),簡稱RNA,係一類由核糖核苷酸通過3',5'-磷酸二酯鍵聚合而成的線性大分子[1]。自然界中的RNA通常是單鏈的,且RNA中最基本的四種鹼基爲A(腺嘌呤)、U(尿嘧啶)、G(鳥嘌呤)、C(胞嘧啶)[註 1],相對的,與RNA同爲核酸的DNA通常是雙鏈分子,且含有的含氮鹼基爲A(腺嘌呤)、T(胸腺嘧啶)、G(鳥嘌呤)、C(胞嘧啶)四種。

RNA有着多種多樣的功能,可在遺傳編碼翻譯、調控、基因表達等過程中發揮作用。按RNA的功能,可將RNA分爲多種類型。比如,在細胞生物中,mRNA(信使RNA)爲遺傳信息的傳遞者,它能夠指導蛋白質的合成。因爲mRNA有編碼蛋白質的能力,它又被稱爲編碼RNA。而其他沒有編碼蛋白質能力的RNA則被稱爲非編碼RNA(ncRNA)。它們或通過催化生化反應,或通過調控或參與基因表達過程發揮相應的生物學功能。比如,tRNA(轉運RNA)在翻譯過程中起轉運RNA的作用,rRNA(核糖體RNA)於翻譯過程中起催化肽鏈形成的作用,sRNA(小RNA)起到調控基因表達的作用。此外,RNA病毒甚至以RNA作爲它們的遺傳物質。

RNA通常由DNA通過轉錄生成。RNA在細胞中廣泛分佈,真核生物的細胞核細胞質粒線體中都有RNA[2]:36

與DNA的比較

 
RNA分子中的含氮鹼基
 
50S核糖體亞單位的3D結構示意圖。rRNA以土黃色表示,蛋白質以藍色表示。活性位點爲rRNA的一個小片段,以紅色標出

RNA的分子結構與DNA非常相似,但是,兩者有以下三個主要不同點:

  • 與通常是雙鏈的DNA不同,RNA通常是單鏈的,而且長度一般比DNA短得多[3][4]。不過,單鏈RNA可以通過摺疊形成雙鏈結構(這樣的雙鏈結構亦被稱爲「」),tRNA中即有這樣的結構。
  • DNA中的戊糖爲脫氧核糖,而RNA中的戊糖爲核糖[5],其區別在於,脫氧核糖的2位碳上連接的是氫原子,而核糖的2位碳上連接的是羥基)。2位碳上的羥基降低了RNA的穩定性,因爲它使得RNA更易被水解。
  • 在DNA中,與腺嘌呤(A)互補的含氮鹼基是胸腺嘧啶(T),而在RNA中,與腺嘌呤(A)互補的含氮鹼基是尿嘧啶(U),它比胸腺嘧啶少了一個甲基[6]

與DNA相似,大部分有生物活性的RNA,包括mRNAtRNArRNAsnRNA,以及其他一些非編碼RNA,雖然是單鏈,但含有自我互補的序列,能使得它們能進行摺疊[7],形成互補雙鏈結構(莖)。對RNA的分析表明,它們有着相對更複雜的結構。和DNA不同,RNA的二級結構並不是單純的雙螺旋,而由一系列短的二級結構構成。通過這些短的二級結構的組合,RNA甚至可以擁有與蛋白質相似的結構,並像那樣催化化學反應(這樣的RNA被稱爲核酶[8]。比如,對核糖體進行分析表明,其催化成肽反應的活性位點完全由RNA構成[9]

結構

 
siRNA(小干擾RNA)中的鹼基互補配對(圖中省略了氫原子)

RNA的單體爲核糖核苷酸,其中的戊糖爲核糖,依系統命名法可將其中的碳原子從1'編號至5'。含氮鹼基與1'碳原子相連。RNA中最基本的四種鹼基分別爲A(腺嘌呤)、U(尿嘧啶)、G(鳥嘌呤)、C(胞嘧啶)。其中,腺嘌呤和鳥嘌呤爲雙環的嘌呤,尿嘧啶和胞嘧啶爲單環的嘧啶。磷酸基團與一個核糖殘基的3'碳原子相連,與下一個核糖核苷酸的5'碳原子相連。磷酸基團在生理pH下,並不都能帶上負電荷,因而RNA在生理條件下是帶電荷分子(聚陰離子)。C和G、U和A、G和U之間能夠形成氫鍵[10]。不過,鹼基之間也可能發生其他一些相互作用。比如,在一個凸出部分中,一群腺嘌呤可以互相連接[11],GNRA四環中有一個G-A鹼基對[10]

 
RNA的分子結構

核糖的2位碳上連有羥基爲RNA的一個重要結構特點。這類羥基使得RNA雙鏈的結構應與A型構象最接近[12],不過,在單鏈的某些二核苷酸環境下,也有極小的可能形成DNA最常見的B型螺旋構象[13]。A型構象使得RNA雙鏈的大溝狹窄而深,小溝淺而寬[14]。在RNA分子的構象高度可變區域(即不生成雙鏈結構的區域),2'-OH還能攻擊附近的磷酸二酯鍵,使得核糖-磷酸鏈斷裂[15]

 
端粒酶RNA二級結構

通過轉錄,僅僅能使RNA鏈上帶A、U、G、C四種含氮鹼基[16]不過,轉錄後修飾能夠通過多種途徑對RNA進行改造。比如,轉錄後修飾能夠將稀有鹼基假尿嘧啶英语Pseudouridine(Ψ)加到RNA鏈上。假尿嘧啶與核糖之間的化學鍵是C-C鍵而不是尿嘧啶(U)的C-N鍵。胸腺嘧啶加到RNA鏈上的情形也很常見(最典型的例子是tRNA的TΨC環)[17]。另外,次黃嘌呤也是一種常見的稀有鹼基。次黃嘌呤爲腺嘌呤的脫氨產物,含有次黃嘌呤的核苷被稱爲肌苷(I)。在基因編碼擺動假說中,肌苷有重要的作用[18]

除以上列出的之外,經過編輯的核苷還有100多種[19]。由修飾引發的結構性變化在tRNA中最爲明顯[20],假尿嘧啶與經常在rRNA中出現2'-甲氧基核糖英语2'-O-methylation是最常見的修飾產物[21]。這些修飾的具體作用還沒有完全闡明。不過,值得注意的是,在rRNA中,許多的轉錄後修飾發生在高度功能化的區域,比如肽基轉移酶催化中心以及亞基結合部位,似乎說明轉錄後修飾對RNA發揮正常功能來說相當重要[22]

具有催化功能的單鏈RNA分子,和蛋白質相類似,需要特殊的RNA三級結構英语Nucleic acid tertiary structure。通過分子內氫鍵形成的二級結構原件構成了三級結構的框架。二級結構形成了許多可識別的「結構域」——比如莖環結構、膨大結構(bulges)、內環結構[23]。因爲RNA分子帶電荷,不少二級結構和三級結構需要Mg2+等金屬離子來進行穩定[24]

自然界中的RNA均是由D-核糖核苷酸聚合而成的D-RNA。使用L-核糖核苷酸則可合成L-RNA。L-RNA對RNA酶的耐受力要強得多[25]

合成與修飾

RNA的合成一般由RNA聚合酶催化。RNA聚合酶以DNA爲模板,通過轉錄合成RNA。轉錄起始於RNA聚合酶與啓動子的結合(啓動子一般位於基因的上游)。因爲RNA聚合酶自帶解旋酶活性,僅依靠RNA聚合酶即可實現DNA雙鏈的解開。轉錄過程中,RNA聚合酶以3'端至5'端的方向讀取DNA模板鏈,並以5'端到3'端的方向合成與之反向平行互補的RNA鏈。轉錄的終止由終止子介導。原核生物的終止子有兩類:簡單終止子與ρ因子依賴性終止子。簡單終止子僅靠RNA形成二級結構即可終止轉錄,而後者在ρ因子的作用下才可以使轉錄終止。真核生物的轉錄終止則與轉錄後修飾密切相關[2]:323[26][27]:531-535

在真核生物中,RNA的初始轉錄物英语Primary transcript通常會經過轉錄後修飾。比如,真核生物的mRNA大都會被加上Poly(A)尾(多腺嘌呤尾巴)以及5'端帽,mRNA前體中含有的內含子序列也會被剪接體切除[27]:580-581

一些RNA是由RNA複製酶(RNA依賴性RNA聚合酶)以RNA爲模板催化合成的。比方說,RNA病毒通過RNA複製酶複製其遺傳物質[28]。另外,RNA複製酶亦參與了眾多生物體的RNA干涉過程[29]

RNA的種類

總覽

 
鎚頭狀核酶英语Hammerhead ribozyme,一種能夠對RNA進行剪切的核酶的結構圖。

mRNA爲攜帶遺傳信息的RNA,它所攜帶的遺傳信息由核糖體讀取,並指導蛋白質合成。mRNA的序列決定了轉譯出的多肽鏈的氨基酸序列[30]。然而,絕大部分的RNA並不編碼蛋白質(真核生物有大約97%的轉錄產物不編碼蛋白質[31][32][33][34])。這樣的RNA被稱爲非編碼RNA(ncRNA)。它們可能由相應的基因編碼(這樣的基因叫RNA基因),也可以由mRNA的內含子演化而成[35]。最常見的非編碼RNA當屬tRNA和rRNA,它們都參與轉譯過程[6]。非編碼RNA亦參與基因表達調控(比如轉錄後修飾等過程)。也有一些RNA具有催化化學反應的作用,比如對RNA進行剪接[36]、催化多肽鏈的合成[9],這類RNA即爲核酶。

按長度分

根據RNA鏈的長度,可將RNA分爲小RNA(sRNA)和長鏈RNA(long RNA)[37]。一般地,小RNA是指長度小於200nt的RNA,長鏈RNA是指長度大於200nt的RNA[38]。長鏈RNA,也叫大RNA(large RNA),主要包括長鏈非編碼RNA(lncRNA)和mRNA。小RNA主要包括5.8S rRNA5S rRNA、tRNA、miRNA(微RNA)、siRNA(小干擾RNA)、snoRNA(小核仁RNA)、snRNA(小核RNA)、scRNA(細胞質小RNA)[2]:49-50

在轉譯過程中

mRNA攜帶遺傳信息,核糖體會讀取其所攜帶的遺傳信息,並合成相應的蛋白質。核糖體以三聯密碼子的形式讀取mRNA上的遺傳信息,每一個三聯密碼子對應一個多肽鏈的氨基酸(終止密碼子除外)。在真核細胞中,轉錄出的mRNA前體需要經過加工才能成爲成熟的mRNA。加工過程會切除掉mRNA前體的內含子區(不編碼的區域)。mRNA隨後會從細胞核中轉移到細胞質中,並與核糖體結合,在tRNA的幫助下,由核糖體讀取其遺傳信息並合成蛋白質。原核生物無成形細胞核,擬核和細胞質無明確界限,在轉錄還未完成時,核糖體就已經與mRNA結合,並開始轉譯過程,而且轉錄完成後,mRNA就會很快被核酸酶攻擊降解,降解時轉譯過程往往還沒有停止[30]

tRNA長約80nt,攜帶氨基酸至核糖體上,爲肽鏈的延伸提供底物。一個tRNA有氨基酸結合區域(5' CCA 3')以及可以與對應密碼子互補的反密碼子區[35]

核糖體RNA構成了核糖體的催化核心。真核生物的核糖體包含18S、5.8S、28S以及5S rRNA(原核生物的核糖體則包含16S、5S、23S rRNA)。真核生物的三種rRNA在核仁中合成,另外一種則在核基質中合成。在細胞質中,rRNA和蛋白質裝配形成一種核糖核蛋白複合物,即核糖體。核糖體與mRNA結合,並催化蛋白質的合成,一條mRNA鏈可同時與多個核糖體結合[30]。典型真核生物中的RNA幾乎都是rRNA。

tmRNA(信使—轉運RNA)在許多細菌色素體中都有分佈。它標記由缺少終止密碼子的mRNA編碼的蛋白質,使其降解。同時,它還能阻止核糖體的停止[39]

Regulatory RNAs

Several types of RNA can downregulate gene expression by being complementary to a part of an mRNA or a gene's DNA.[40][41] MicroRNAs (miRNA; 21-22 nt) are found in eukaryotes and act through RNA interference (RNAi), where an effector complex of miRNA and enzymes can cleave complementary mRNA, block the mRNA from being translated, or accelerate its degradation.[42][43]

While small interfering RNAs (siRNA; 20-25 nt) are often produced by breakdown of viral RNA, there are also endogenous sources of siRNAs.[44][45] siRNAs act through RNA interference in a fashion similar to miRNAs. Some miRNAs and siRNAs can cause genes they target to be methylated, thereby decreasing or increasing transcription of those genes.[46][47][48] Animals have Piwi-interacting RNAs (piRNA; 29-30 nt) that are active in germline cells and are thought to be a defense against transposons and play a role in gametogenesis.[49][50]

Many prokaryotes have CRISPR RNAs, a regulatory system similar to RNA interference.[51] Antisense RNAs are widespread; most downregulate a gene, but a few are activators of transcription.[52] One way antisense RNA can act is by binding to an mRNA, forming double-stranded RNA that is enzymatically degraded.[53] There are many long noncoding RNAs that regulate genes in eukaryotes,[54] one such RNA is Xist, which coats one X chromosome in female mammals and inactivates it.[55]

An mRNA may contain regulatory elements itself, such as riboswitches, in the 5' untranslated region or 3' untranslated region; these cis-regulatory elements regulate the activity of that mRNA.[56] The untranslated regions can also contain elements that regulate other genes.[57]

In RNA processing

 
Uridine to pseudouridine is a common RNA modification.

Many RNAs are involved in modifying other RNAs. Introns are spliced out of pre-mRNA by spliceosomes, which contain several small nuclear RNAs (snRNA),[6] or the introns can be ribozymes that are spliced by themselves.[58] RNA can also be altered by having its nucleotides modified to other nucleotides than A, C, G and U. In eukaryotes, modifications of RNA nucleotides are in general directed by small nucleolar RNAs (snoRNA; 60-300 nt),[35] found in the nucleolus and cajal bodies. snoRNAs associate with enzymes and guide them to a spot on an RNA by basepairing to that RNA. These enzymes then perform the nucleotide modification. rRNAs and tRNAs are extensively modified, but snRNAs and mRNAs can also be the target of base modification.[59][60] RNA can also be methylated.[61][62]

RNA genomes

Like DNA, RNA can carry genetic information. RNA viruses have genomes composed of RNA that encodes a number of proteins. The viral genome is replicated by some of those proteins, while other proteins protect the genome as the virus particle moves to a new host cell. Viroids are another group of pathogens, but they consist only of RNA, do not encode any protein and are replicated by a host plant cell's polymerase.[63]

In reverse transcription

Reverse transcribing viruses replicate their genomes by reverse transcribing DNA copies from their RNA; these DNA copies are then transcribed to new RNA. Retrotransposons also spread by copying DNA and RNA from one another,[64] and telomerase contains an RNA that is used as template for building the ends of eukaryotic chromosomes.[65]

Double-stranded RNA

Double-stranded RNA (dsRNA) is RNA with two complementary strands, similar to the DNA found in all cells. dsRNA forms the genetic material of some viruses (double-stranded RNA viruses). Double-stranded RNA such as viral RNA or siRNA can trigger RNA interference in eukaryotes, as well as interferon response in vertebrates.[66][67][68][69]

RNA生物學中的重大發現

 
羅伯特·W·霍利與他的研究團隊在一起

對RNA的研究催生了許多重大的生物學發現,諾貝爾獎亦數次垂青對RNA進行研究的科學家。1868年,弗雷德里希·米歇爾發現了核酸。因爲他是在細胞核中發現這種物質的,所以,他把這種物質稱爲「核素」(nuclein)[70]。後來,人們發現沒有成形細胞核的原核細胞仍然含有核酸。早在1939年,就有人提出RNA可能參與蛋白質合成[71]塞韋羅·奧喬亞因發現一種能夠在實驗室中合成RNA的酶而與阿瑟·科恩伯格獲得1959年諾貝爾生理醫學獎[72]。然而,由奧喬亞發現的酶(多核苷酸磷酸化酶英语Polynucleotide phosphorylase)隨後卻被證明是負責RNA降解,而不是RNA合成的。1956年,亞歷山大·里奇大衛·戴維斯使兩條RNA進行雜交,並製得了第一批RNA晶體。該晶體的結構可通過X射線衍射確定[73]

1965年,羅伯特·W·霍利測定了長77nt(nt:核苷酸)的酵母菌tRNA的序列[74],這使得他與哈爾·葛賓·科拉納馬歇爾·沃倫·尼倫伯格獲得了1968年的諾貝爾生理醫學獎。1967年,卡爾·烏斯提出可能存在具有催化功能的RNA。他還認爲,早期的生命(自我複製的分子)可能僅用RNA來進行催化和攜帶遺傳信息(即RNA世界假說)[75][76]

1970年代早期,發現了逆轉錄病毒以及逆轉錄酶,證明酶可以用RNA爲模板合成DNA(這和通常的遺傳信息傳遞方向相反)。戴維·巴爾的摩羅納托·杜爾貝科霍華德·馬丁·特明因此獲得了1975年諾貝爾生理醫學獎。1976年,瓦爾特·费爾斯與他的研究團隊發現了第一段與RNA病毒MS2噬菌體英语Bacteriophage MS2基因組互補的核苷酸序列[77]

1977年,在哺乳動物病毒以及細胞基因中發現了內含子以及RNA剪接現象。這一發現使得理察·羅伯茨菲利普·夏普獲得1993年諾貝爾生理醫學獎。核酶最早於1980年代早期發現,使西德尼·奧特曼托馬斯·切赫兩人獲1989年諾貝爾化學獎。1990年,對矮牽牛花的實驗表明,引入的基因可以沉默植物體原有的基因,這一現象即RNA干擾[78][79]

1990年左右,發現一種22nt長的RNA在秀麗隱桿線蟲的發育過程中發揮作用,這種RNA即微RNA(microRNA)[80]。對RNA干擾的研究使得安德魯·法厄克雷格·梅洛獲得2006年生理醫學獎。有趣的是,當年的諾貝爾化學獎亦頒給了對RNA轉錄進行研究的羅傑·科恩伯格。基因調控RNA的發現使得人們開始研發以RNA爲化學本質(比如siRNA(小干擾RNA))的藥物來使得基因沉默[81]

See also

註釋

  1. ^ 通過轉錄後修飾,RNA可能會帶上假尿嘧啶英语Pseudouridine(Ψ)這樣的稀有鹼基

參考

  1. ^ David Hames & Nigel Hooper. Instant Notes in Biochemistry (導讀本) 3rd edition. 科学出版社. 2005: 193. ISBN 978-7-03-025218-0. 
  2. ^ 2.0 2.1 2.2 查錫良 藥立波. 生物化學與分子生物學 第八版. 人民衛生出版社. 2013. ISBN 978-7-117-17214-1. 
  3. ^ RNA: The Versatile Molecule. University of Utah. 2015. 
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