蛋白序列可以和DNA序列不对应

        只有弄清蛋白中氨基酸的排列顺序和编码此蛋白的DNA之间的直接、线性的关系，才有可能解决医学研究所遇到的遗传学问题。实际上，DNA链和蛋白序列的线性性质，是普适遗传密码（universal  genetic  code）的一个基本特征。然而，8月7日SCIENCE一篇文章中，美国Ludwig癌  症研究所(Ludwig  Institute  for  Cancer  Research，LICR)布鲁塞尔小组和西雅图Fred  Hutchinson  癌症研究中心（Fred  Hutchinson  Cancer  Research  Center,  FHCRC）研究人员宣布，一种蛋白可以被重新排列，不再与编码它的DNA呈线性对应关系。

        基因由编码蛋白的DNA序列（外显子）和不编码蛋白的DNA序列（内含子）相间排列组成。蛋白编码的第一步是将DNA转录为RNA，然后RNA通过剪接过程将内含子去掉，外显子直线连接起来，形成翻译蛋白的模板。论文高级作者Van  den  Eynde博士说：“直到现在，人们一直认为DNA和蛋白的线性对应关系只会受到RNA剪接的干扰。免疫学中蛋白也会发生拼接事件，不同的蛋白片段，肽段也可能以有悖于‘父母’双亲蛋白的排列顺序排列在一起。”

        Van  den  Eynde博士在其文章中提出的一种新奇的现象发生在抗原加工和提呈程序（antigen  processing）中产生的抗原肽，抗原肽作为一杆红旗，指导免疫系统破坏靶细胞。

        科学家的惯性思维是，当T淋巴细胞识别“非常态”细胞（肿瘤细胞、病毒感染细胞或者同种异体捐助的细胞）表面提呈的抗原肽时，免疫系统攻击“非常态”细胞。抗原提呈细胞捕获抗原，细胞中的蛋白酶体（proteasomes）将外源蛋白切割为肽段，然后提呈到细胞表面，CD8+T细胞识别被提呈的抗原肽，摧毁“非常态“细胞。

        Belgium/USA研究小组发现蛋白酶体也可以以编码蛋白的DNA序列模板相反的顺序，将肽段拼接在一起。这样的机制使来自一个蛋白的数量有限的抗原有可能形成成千上万种序列形式。

        LICR  Brussels  Branch鉴定出的第一个人类癌症特异抗原序列，有利于世界临床抗特异性癌症疫苗的研究。此研究结果描绘的机制扩大了可以形成单一蛋白抗原肽的数量，拓宽了抵抗癌症和传染病的肽段疫苗的使用范围。

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.