自然杂志6月15日刊登一个新研究，科学家发现一种改变遗传密码的全新方法，这一方法可协助研究人员从根本上扭转不断恶化的遗传疾病，如囊肿化纤维组织症，肌肉萎缩症和多种类型的癌症，因而，其意义重大。
基因中的遗传密码是“告诉”细胞如何合成特定蛋白质的一系列指令。信使RNA（mRNA）是机体蛋白合成的中心，它从DNA分子转录过程中携带遗传指令，然而指导核糖体合成蛋白质。科研人员首次人为地修改信使RNA，进而改变用于合成蛋白质的原有遗传指令，最终结果是合成一种不符合原指令的新蛋白。
罗切斯特医学中心生化和生物物理研究所的所长Robert Bambara博士称，对编码基因合成特定蛋白的调控能力是现代医学的新奇迹，这一实用技术可用于抑制个体患遗传疾病的趋势，通常情况下，遗传疾病可引起个体特定功能衰退，有些致命遗传疾病会一直影响不同患者的寿命。
蛋白质的合成不是一个极其准确过程，有时候连准确也算不上。DNA和信使RNA中高频率的突变导致错义蛋白质的合成，后者可能产生严重的危害。在这项研究中，研究人员把注意力都集中在1种变异类型——mRNA分子具有“过早”终止信号（“过早”终止子），在蛋白质合成中，“过早”终止子命令细胞停止"阅读"遗传信息指令，导致合成一条不完整的短蛋白。
研究人员通过把终止子转变成"通过"信号的新技术改变mRNA遗传信息，结果，细胞能“阅读”完整的遗传指令，合成了正常的全长蛋白质，这一实验成功地在体外和存活酵母细胞中进行。
生化和生物物理研究所副教授 Yi-Tao Yu博士称，这一发现令人惊奇，从来没人想到我们能改变终止密码子，而且转录过程不受影响就像对终止密码子的修改从未发生一样。
这一发现非常重要，据估计，大约1/3的遗传疾病是由于“过早”终止子引起的，在此研究的基础上，新的治疗方案有助于机体“覆盖”终止密码子，进而合成适量的全长蛋白。全长蛋白的缺失会引起许多遗传疾病，如囊肿化纤维组织症和不同类型的癌症。
Yi-Tao Yu博士和论文第一作者John Karijolich博士用其它类型的RNA（指导RAN）去修改信使RNA,这类指导RNA是结合在RNA的特定序列仅改变一个特定碱基的小分子RNA。“我们可利用指导RNA锁定基因组的1个特异位点，进而做出定向的变异。” Bambara如此地说。
研究小组开发出一种人为改造的指导RNA，它可以按照设置对mRNA分子的特定终止子进行定向改变。
罗切斯特学校毕业生Karijolich开展上述试验，他说，改造后的指导RNA可定向识别终止密码子，并引起终止密码子向所需的方向改变，这一手段起到很明显的效果。过去人们一直认为指导RNA不能识别mRNA，因此，不相信它能定向改变mRNA，然而，我们的研究提出一个问题——类似的过程是否能重复地发生？
Yi-Tao Yu博士说，之前的研究也提供许多改变遗传密码的方法，而我们的方法独特之处是在RNA水平修改特定的位点。同时，我们也可在细胞中表达人为改造的指导RNA，用它对单一的、特定的位点进行修改。
通过这一方法，修改后信使RNA可作为人体细胞合成不同类型蛋白的候选机制。鉴于基因组的复杂性，人类基因数目出奇的少。人体大多数基因编码不止1种蛋白质，mRNA修改可能是人体做到这一点的的一种途径。
Yi-Tao Yu博士计划开展进一步的研究，探究定向mRNA修改是否可重复发生，以及发生机理。
这项研究是美国国立卫生研究院公众医疗研究所（National Institute of General Medical Sciences）资助。（生物探索译）
科学家发现改变遗传密码的新方法
生物探索推荐英语原文
Scientists Override Errant Form of Genetic Signaling for First Time: Changing Genetic 'Red Light' to Green Holds Promise
for Treating Disease
In a new study published June 15 in the journal Nature, scientists discovered an entirely new way to change the genetic code. The findings, though early, are significant because they may ultimately help researchers alter the course of devastating genetic disorders, such as cystic fibrosis, muscular dystrophy and many forms of cancer.
The genetic code is the set of instructions in a gene that tell a cell how to make a specific protein. Central to the body's protein production process is messenger RNA, or mRNA, which takes these instructions from DNA and directs the steps necessary to build a protein. For the first time, researchers artificially modified messenger RNA, and in doing so changed the original instructions for creating the protein. The end result: A different protein than originally called for.
"The ability to manipulate the production of a protein from a particular gene is the new miracle of modern medicine," said Robert Bambara, Ph.D., chair of the Department of Biochemistry and Biophysics at the University of Rochester Medical Center. "This is a really powerful concept that can be used to try to suppress the tendency of individuals to get certain debilitating, and sometimes fatal genetic diseases that will forever change their lives."
Protein production is not a perfect process -- far from it. Frequent mutations or mistakes in DNA and messenger RNA can lead to flawed proteins that have the potential to cause serious harm. In the study, researchers focused on a common type of mutation that occurs when an mRNA molecule contains a pre-mature "stop" signal, known as a pre-mature stop codon. A premature stop codon orders a cell to stop reading the genetic instructions partway through the process, resulting in the creation of an incomplete, shortened protein.
Researchers were able to alter mRNA in a way that turned a stop signal into a "go" signal. As a result, the cell could read the genetic instructions all the way through and create a normal, full-length protein. The team produced these results both in vitro and in live yeast cells.
"This is a very exciting finding," said Yi-Tao Yu, Ph.D., lead study author and associate professor of Biochemistry and Biophysics at the Medical Center. "No one ever imagined that you could alter a stop codon the way we have and allow translation to continue uninterrupted like it was never there in the first place."
The findings are important because current estimates suggest that approximately one third of genetic diseases are caused by the presence of pre-mature stop codons that result in shortened proteins. The results could aid the development of treatment strategies designed to help the body override stop codons and produce adequate amounts of full-length proteins, whose absence causes diseases like cystic fibrosis and contributes to different types of cancer.
Yu, along with first author John Karijolich, Ph.D., used another type of RNA -- guide RNA -- to modify messenger RNA. Guide RNAs are short RNAs that bind to specific sequences in RNA and allow just one particular site to be modified. "Guide RNAs give us tremendous power to zero in on one spot in the genome and make very targeted changes," noted Bambara.
The team developed an artificial guide RNA and programmed it to target and change a specific stop codon in an mRNA.
"The fact that this strategy worked -- that the guide RNA we created found its way to its target, the stop codon, and directed the desired structure change -- is pretty remarkable. Guide RNAs weren't thought to have access to messenger RNA, so no one believed they could target messenger RNA for modification," said Karijolich, who conducted the research as a graduate student at Rochester, but is now a postdoctoral fellow in the Department of Biochemistry at the Robert Wood Johnson Medical School. "Our results bring up the question of whether a similar process may be happening naturally."
"Previous research has presented other ways to modify the genetic code, but what is really unique about our method is that it is at the RNA level and it is site specific. We can express the artificial guide RNA in a cell and direct it to make a modification at a single site and only that site," said Yu.
Altering messenger RNA in this way may be another mechanism human cells use to create many different types of proteins. Given our complexity, humans have surprisingly few genes. While it is well established that the majority of human genes code for more than one protein, mRNA modification may be an unrealized way that humans are able to do this.
Yu plans to pursue this research further, studying whether and how targeted mRNA modification is happening naturally.
The study was funded by the National Institute of General Medical Sciences at the National Institutes of Health.
