Ribozymes and DNAzymes-- ancient catalytic activities for modern biomedical and other utility

核酶和脱氧核糖核酸酶——现代生物医学和其他用途的古老催化活性

• 批准号: 105785-2012
• 负责人: Sen, Dipankar
• 金额: $ 5.17万
• 依托单位: Simon Fraser University
• 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=569113
• 关键词: Ribozymes; DNAzymes; ancient; catalytic; activities

My laboratory conducts broad-ranging research on the fundamental properties of DNA and RNA, the shared genetic material of all living organisms. Particularly, we are interested in the catalytic properties of RNA/DNA. Defining the range of catalysis available to RNA and DNA enzymes (ribozymes and DNAzymes) is crucial for understanding how early bio-catalytic systems evolved on earth; how quite different biopolymers (DNA/RNA versus proteins) can meet specific catalytic challenges; and, for obtaining powerful new reagents that can be applied towards disease bio-sensing, therapeutics, as well as other, often unanticipated, uses. Two very interesting and unexpected catalytic properties of RNA/DNA have been discovered in my laboratory: (a) that certain catalytic DNAs (DNAzymes) are able to harness light (at wavelengths not harmful to human DNA) to repair cancer-causing thymine dimer lesions in DNA itself. We have recently succeeded in creating variant DNAzymes that are able to utilize visible rather than UV light for their DNA repair activity. And, (b) that large numbers of RNAs and DNAs are able to form tight complexes with heme, an important and versatile metabolic cofactor. These DNA/RNA-complexes then surprisingly catalyze key oxidative reactions, that are normally associated with highly specialized heme-utilizing protein enzymes. This proposal has two goals: The first will be to dissect the catalytic properties of guanine-rich RNAs & DNAs that form tight complexes with heme. We will determine precisely how heme-ribozymes structurally and mechanistically replicate the properties of heme proteins; and, how a heme-ribozyme could be designed to oxidize "difficult" substrates. Our second goal will be to conduct in vitro selection, characterization, and practical utilization of DNAzymes that use visible light to repair thymine dimer lesions in DNA. Specifically, we will determine whether a photolyase DNAzyme can ever be as efficient as its protein counterparts; also we will design medically relevant photolyase DNAzymes, that can be applied topically to human skin to offer protection against DNA damage by ultraviolet light.

我的实验室对所有生物共有的遗传物质DNA和RNA的基本特性进行了广泛的研究。我们尤其对RNA/DNA的催化特性感兴趣。确定RNA和DNA酶（核酶和DNAzymes）的催化范围对于理解地球上早期生物催化系统的进化至关重要；不同的生物聚合物（DNA/RNA与蛋白质）如何应对特定的催化挑战；并且，获得强大的新试剂，可以应用于疾病生物传感、治疗以及其他通常意想不到的用途。