想要理解一些醫(yī)學(xué)基礎(chǔ)研究的問(wèn)題，人們經(jīng)常要依靠蛋白質(zhì)序列和編碼這個(gè)蛋白質(zhì)的DNA之間直接,、線性的關(guān)系,。實(shí)際上，DNA和蛋白質(zhì)序列的共線性被認(rèn)為所有遺傳密碼的基本特征,。同一篇報(bào)道見：蛋白序列可以和DNA序列不對(duì)應(yīng)
然而,，一篇發(fā)表在8月7日的Science上的文章發(fā)現(xiàn)了一種能被重新組合的蛋白質(zhì)，因此它與編碼它的DNA就不再是共線性的了,。完成這篇文章的研究小組來(lái)自全球Ludwig癌癥研究所布魯塞爾分所(LICR)和以西雅圖為基地的Hutchinson癌癥研究中心的科學(xué)家,。
一段基因的DNA鏈上，既有編碼（蛋白質(zhì)）DNA序列,，也散落著非編碼DNA序列,。制造蛋白質(zhì)的第一步是將整個(gè)基因序列忠實(shí)地轉(zhuǎn)錄為RNA序列。而后就是RNA被拼接的過(guò)程,。這些散落非編碼序列被移除,，編碼序列便集合成線性方式從而形成了RNA翻譯為蛋白質(zhì)的模版,。
這篇文章的通訊作者，LICR的Benoit Van den Eynde博士說(shuō)：“到目前為止,，僅RNA拼接這一事實(shí)的存在就打破了DNA和蛋白質(zhì)共線性這種說(shuō)法,。這項(xiàng)新研究表明蛋白質(zhì)也有拼接現(xiàn)象，有時(shí)甚至產(chǎn)生的蛋白質(zhì)片段或多肽以與親本相反的方向拼接在一起,。根據(jù)Van den Eynde博士的說(shuō)法,，這種新穎的現(xiàn)象常發(fā)生在一種名為”抗原加工“的生理過(guò)程中，抗原加工會(huì)產(chǎn)生抗原多肽,，而這會(huì)讓靶細(xì)胞被標(biāo)上“紅旗”標(biāo)志,，以便免疫系統(tǒng)將其摧毀。
當(dāng)T淋巴細(xì)胞識(shí)別出細(xì)胞表面存在抗原多肽時(shí),，免疫系統(tǒng)便將其認(rèn)為異種細(xì)胞,，并開始攻擊，這些異種細(xì)胞包括腫瘤細(xì)胞,，病毒感染的細(xì)胞和來(lái)源于捐贈(zèng)人的細(xì)胞,。抗原們由蛋白酶體的成員加工產(chǎn)生,，蛋白酶體也是細(xì)胞機(jī)制的一部分,。這些蛋白酶體將外來(lái)蛋白切割成多肽，并將其陳列在細(xì)胞表面供CD8+ T淋巴細(xì)胞發(fā)揮識(shí)別和摧毀作用,。然而,，比利時(shí)/美國(guó)的一個(gè)研究小組發(fā)現(xiàn)蛋白酶體還可以拼接這些肽段，拼接的方向與編碼這些蛋白質(zhì)的DNA模版鏈方向相反,。這使得來(lái)源于一種蛋白的抗原有可能達(dá)到數(shù)千種之多,。
第一個(gè)人類癌癥特異抗原就是在LICR布魯塞爾分所鑒定得到的，這使抗原特異的癌癥疫苗得以研發(fā),，目前有關(guān)這種疫苗的臨床實(shí)驗(yàn)已在世界范圍內(nèi)蓬勃開展起來(lái),。這項(xiàng)研究描述了單一蛋白可產(chǎn)生數(shù)目眾多的抗原多肽這一現(xiàn)象的機(jī)制，由此可擴(kuò)大癌癥和感染性疾病的肽類疫苗的應(yīng)用,。
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.
