只有弄清蛋白中氨基酸的排列順序和編碼此蛋白的DNA之間的直接,、線性的關(guān)系,，才有可能解決醫(yī)學(xué)研究所遇到的遺傳學(xué)問(wèn)題。實(shí)際上,，DNA鏈和蛋白序列的線性性質(zhì),，是普適遺傳密碼（universal genetic code）的一個(gè)基本特征。然而,，8月7日SCIENCE一篇文章中,，美國(guó)Ludwig癌 癥研究所(Ludwig Institute for Cancer Research，LICR)布魯塞爾小組和西雅圖Fred Hutchinson 癌癥研究中心（Fred Hutchinson Cancer Research Center, FHCRC）研究人員宣布,，一種蛋白可以被重新排列,，不再與編碼它的DNA呈線性對(duì)應(yīng)關(guān)系。
基因由編碼蛋白的DNA序列（外顯子）和不編碼蛋白的DNA序列（內(nèi)含子）相間排列組成,。蛋白編碼的第一步是將DNA轉(zhuǎn)錄為RNA,，然后RNA通過(guò)剪接過(guò)程將內(nèi)含子去掉，外顯子直線連接起來(lái),，形成翻譯蛋白的模板,。論文高級(jí)作者Van den Eynde博士說(shuō)：“直到現(xiàn)在，人們一直認(rèn)為DNA和蛋白的線性對(duì)應(yīng)關(guān)系只會(huì)受到RNA剪接的干擾,。免疫學(xué)中蛋白也會(huì)發(fā)生拼接事件,，不同的蛋白片段，肽段也可能以有悖于‘父母’雙親蛋白的排列順序排列在一起,。”
Van den Eynde博士在其文章中提出的一種新奇的現(xiàn)象發(fā)生在抗原加工和提呈程序（antigen processing）中產(chǎn)生的抗原肽,，抗原肽作為一桿紅旗，指導(dǎo)免疫系統(tǒng)破壞靶細(xì)胞,。
科學(xué)家的慣性思維是,，當(dāng)T淋巴細(xì)胞識(shí)別“非常態(tài)”細(xì)胞（腫瘤細(xì)胞、病毒感染細(xì)胞或者同種異體捐助的細(xì)胞）表面提呈的抗原肽時(shí),，免疫系統(tǒng)攻擊“非常態(tài)”細(xì)胞,。抗原提呈細(xì)胞捕獲抗原,，細(xì)胞中的蛋白酶體（proteasomes）將外源蛋白切割為肽段,，然后提呈到細(xì)胞表面，CD8+T細(xì)胞識(shí)別被提呈的抗原肽,，摧毀“非常態(tài)“細(xì)胞,。
Belgium/USA研究小組發(fā)現(xiàn)蛋白酶體也可以以編碼蛋白的DNA序列模板相反的順序,，將肽段拼接在一起。這樣的機(jī)制使來(lái)自一個(gè)蛋白的數(shù)量有限的抗原有可能形成成千上萬(wàn)種序列形式,。
LICR Brussels Branch鑒定出的第一個(gè)人類癌癥特異抗原序列,，有利于世界臨床抗特異性癌癥疫苗的研究。此研究結(jié)果描繪的機(jī)制擴(kuò)大了可以形成單一蛋白抗原肽的數(shù)量,，拓寬了抵抗癌癥和傳染病的肽段疫苗的使用范圍,。
英文原文:
Protein splicing upsets the DNA colinearity paradigm
September 8, Brussels and New York -- Understanding medical research problems often relies on the direct, linear relationship between the sequence of a protein and the DNA encoding that protein. In fact, colinearity of DNA and protein sequences is thought to be a fundamental feature of the universal genetic code. However, a paper published today in Science by a team from the Brussels Branch of the global Ludwig Institute for Cancer Research (LICR) and the Seattle-based Fred Hutchinson Cancer Research Center (FHCRC), shows that a protein can be rearranged so that it is no longer colinear with its encoding DNA.
Genes have stretches of (protein) coding DNA sequences interspersed with stretches of non-coding DNA sequences. The first step in making the protein is the faithful transcription of the entire gene's sequence into an RNA sequence. The RNA is then 'spliced' such that the non-coding sequences are removed and the coding sequences are assembled in a linear fashion to form the template for translation from RNA to protein.
"Until now it was thought that colinearity of DNA and protein sequences was only interrupted by RNA splicing," says LICR's Dr. Benoit Van den Eynde, the study's senior author. "This new study shows that protein splicing also occurs, and may even result in protein fragments, or peptides, being spliced together in the order opposite to that which occurs in the parental protein."
According to Dr. Van den Eynde, this novel phenomenon occurs during the physiological function of 'antigen processing,' which produces antigenic peptides; the 'red flags' that mark cells for destruction by the immune system.
The immune system attacks 'foreign' cells - be they tumor cells, virally infected, or donated by another person - when T lymphocytes recognize antigenic peptides displayed on the cell surface. The antigens are created by 'proteasomes,' components of the cell machinery that cut foreign proteins into peptides that are then displayed on the cell surface for recognition and destruction by CD8+ T lymphocytes. However, the Belgium/USA team has found that proteasomes can also splice the peptide fragments together in a reverse order to that encoded by the protein's DNA sequence template. This takes the possible number of antigens from any one protein into potentially thousands of sequence configurations.
The sequence of the first human cancer-specific antigen, which was identified at the LICR Brussels Branch, has allowed the development of antigen-specific cancer vaccines that are in clinical trials around the world. This study describes a mechanism that significantly extends the number of antigenic peptides that can be produced from a single protein, and therefore widens the applicability of peptide vaccines against cancer and infectious diseases.
