APE1 as a Novel Mammalian Endoribonuclease

APE1 作为一种新型哺乳动物核糖核酸内切酶

• 批准号: 227158-2012
• 负责人: Lee, Chow
• 金额: $ 3.5万
• 依托单位: University of Northern British Columbia
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2015
• 资助国家: 加拿大
• 起止时间: 2015-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=570248
• 关键词: APE1; Novel; Mammalian; Endoribonuclease

One of the most fundamental activities in living systems is to copy their genetic information (DNA) into proteins, the molecular machines that carry out most of the biological functions that keep an organism alive. The copying of DNA into proteins occurs in two steps: first, DNA is copied into mRNA (messenger ribonucleic acid; chemically similar to DNA); second, mRNA is used as a template to make specific proteins. The amount of proteins is therefore dependent on the amount of mRNAs. An excess or shortage of many proteins due to changes in the abundance of mRNA can lead to diseases, such as cancer. The abundance of mRNAs is highly dependent on the rate of its degradation. An understanding of how the mRNA degradation machinery works is therefore important for increasing our basic scientific knowledge of molecular biology, as well as for revealing information on the pathogenesis of some human diseases. It has been widely believed that mammalian mRNAs are primarily degraded from the ends of the molecules. However several recent reports including a publication from our own laboratory are beginning to challenge this view. These report have shown that mRNAs can also be degraded through cleavage in the middle of the molecules - a process known as endonucleolytic cleavage. Enzymes that initiate endonucleolytic cleavage are called endoribonucleases. Our laboratory has recently identified APE1 as an endoribonuclease that cleaves c-myc mRNA in a test tube. We have also shown that APE1 can influence the abundance and longevity of c-myc mRNA in cells. The goals of our proposed research are to determine the RNA targets of APE1 in cells, and to ascertain whether it is an important endoribonuclease for controlling the abundance of various RNA molecules. Results generated from these studies have high potential to advance our knowledge of gene expression, as well as possibly leading to the use of the enzyme or its properties in RNA degradation technology.

生命系统中最基本的活动之一是将其遗传信息（DNA）复制到蛋白质中，蛋白质是执行维持生物体存活的大部分生物功能的分子机器。 将DNA复制成蛋白质分两步进行：第一步，DNA复制成mRNA（信使核糖核酸;化学上类似于DNA）;第二步，mRNA作为模板制造特定的蛋白质。因此，蛋白质的量取决于mRNA的量。 由于mRNA丰度的变化而导致的许多蛋白质的过量或短缺可能导致疾病，例如癌症。mRNA的丰度高度依赖于其降解速率。 因此，了解mRNA降解机制如何工作对于增加我们的分子生物学基础科学知识以及揭示某些人类疾病的发病机制信息非常重要。 人们普遍认为，哺乳动物mRNA主要从分子末端降解。 然而，最近的几份报告，包括我们自己实验室的一份出版物，开始挑战这一观点。这些报告表明，mRNA也可以通过分子中间的切割而降解-这一过程称为内切核酸切割。启动核酸内切裂解的酶称为核糖核酸内切酶。 我们的实验室最近发现APE 1是一种内切核糖核酸酶，在试管中切割c-myc mRNA。 我们还表明，APE 1可以影响细胞中c-myc mRNA的丰度和寿命。我们提出的研究目标是确定APE 1在细胞中的RNA靶点，并确定它是否是控制各种RNA分子丰度的重要内切核糖核酸酶。从这些研究中产生的结果有很大的潜力，以提高我们的基因表达的知识，以及可能导致使用的酶或其性质的RNA降解技术。