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DNA structure modification by the Schlafen protein family

Schlafen 蛋白家族对 DNA 结构的修饰

基本信息

批准号：
9238658
负责人：
MICHAEL DAVID
金额：
$ 18.11万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-03-07 至 2019-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9238658
关键词：
ATP phosphohydrolase ATPase Domain Alternative Splicing Antibodies Antineoplastic Agents Antiviral Agents Attention Attenuated Autoimmune Diseases B-DNA Binding Biological Biological Process Biology Caenorhabditis elegans Cancer cell line Cell Line Cells Codon Nucleotides Communicable Diseases DNA DNA Binding DNA Binding Domain DNA Damage DNA Structure Data Derivation procedure Diagnostic Down-Regulation Drosophila genus ERG gene Elements Employee Strikes Family Funding Funding Agency Generations Genes Genetic Goals HIV Hand Human IRF3 gene Immune response Immunologics Infection Infection prevention Innate Immune Response Interferon-alpha Interferons Investigation Kinetics Laboratories Left Length Link Lupus Erythematosus Messenger RNA Modernization Modification N-terminal Nucleic Acid Conformation Nucleic Acids Organism Pathway interactions Pharmacology Physiological Play Poxviridae Process Production Protein Biosynthesis Protein Family Protein Isoforms Proteins Publishing RNA RNA Helicase Research Research Personnel Resistance Resistance development Retroviridae Role Simian virus 40 Structure Surface System Techniques Technology Testing Therapeutic Intervention Time Transfer RNA Vaccine Adjuvant Viral Viral Proteins Virus Virus Diseases Work Yeasts Z-DNA Binding Protein Z-Form DNA adaptive immune response antitumor drug base cancer cell chemotherapeutic agent cytotoxic experimental study genome-wide analysis helicase immunogenic in vivo insight interest member neoplastic cell novel pathogen prevent prospective public health relevance small molecule tool vaccine development

项目摘要

DESCRIPTION (provided by applicant): The innate immune response is not antigen-specific, and is composed of the interferon (IFN) system as well as cell-based anti-pathogen countermeasures that restrict the replication of pathogens. Understanding the innate immune response and the pathways that promote or restrict the kinetics of different steps of infection is essential for devising novel pharmacological strategies for therapeutic intervention during these infectious disease processes, to develop diagnostic tools or to prevent infection. Interferons exert their antiviral effects through the induction of Interferon Stimulated early response Genes (ISGs). An expanding family of such ISGs are the Schlafen (Slfn) genes, which in addition to IFN are also directly induced by pathogen contact with the cells. In our quest to define the biological function of Slfn proteins we discovered that huSlfn11 potently inhibits the production of retroviruses including HIV. Our studies revealed huSlfn11 expression had no effect on the early steps of the infection cycle, but that huSlfn11 protein acts at the very late stages of replication where new viral proteins are synthesized. A striking hallmark of huSlfn11 function is the selective inhibition of the synthesis of virus-encoded proteins, whereas production host cell proteins are apparently unhindered. Most recently, genome-wide screening efforts from two independent laboratories employing dozens of cancer cells lines identified an intriguing correlation between huSlfn11 expression and sensitivity of cells to DDAs. Using cell lines we generated during our previous studies which specifically lack huSlfn11, we find that indeed such cells are resistant to the cytotoxic effects of several classes of DDAs. It is therefore quite reasonable to consider that the development of resistance of tumor cells against DDAs involves the down- regulation of huSlfn11. Finally, our newest studies revealed that huSlfn 5 and 11 have the ability to bind and/or generate Z-DNA. As the structure of the Z-DNA double helix is considerably different from that of B-DNA it supports different interactivity with other molecules, and a few proteins have been identified that selectively bind to Z-DNA but not to B-DNA. It is also notable that unlike B-DNA, Z-DNA is very immunogenic which has not only allowed for the production of highly specific antibodies for research purposes, but has also given rise to anti-Z-DNA antibodies in autoimmune disease such as lupus erythematosus. Although the left-handed Z-DNA and Z-RNA forms were discovered decades ago, their biological role has remained a mystery, largely because little information exists on their formation under physiological conditions. So for several decades not much insight had surfaced on Z-DNA function. In fact, since the end of the 1980s the biology of Z-DNA was not receiving much attention from researchers or funding agencies, and with a few exceptions focused on the role of Z-DNA in genetic instabilities. Our discovery of Z-D/RNA generation by Slfns, a family of interferon-induced antiviral proteins, has the strong potential to place these left-handed nucleic acids into numerous immune response scenarios. Understanding of the biological roles of Z-D/RNA is elementary to exploit their prospective pharmacological possibilities in the development of vaccine adjuvants, anti-viral or anti-neoplastic chemotherapeutics.

描述（由申请人提供）：先天免疫反应不是抗原特异性的，由干扰素（IFN）系统以及限制病原体复制的基于细胞的抗病原体对策组成。了解先天免疫反应以及促进或限制感染不同步骤动力学的途径对于设计在这些传染病过程中进行治疗干预的新药理学策略、开发诊断工具或预防感染至关重要。干扰素通过诱导干扰素刺激早期反应基因（ISG）发挥抗病毒作用。 Schlafen (Slfn) 基因是此类 ISG 的一个不断扩大的家族，除了 IFN 之外，该基因也由病原体与细胞接触直接诱导。在我们探索 Slfn 蛋白的生物学功能的过程中，我们发现 huSlfn11 能有效抑制包括 HIV 在内的逆转录病毒的产生。我们的研究表明 huSlfn11 表达对感染周期的早期阶段没有影响，但 huSlfn11 蛋白在合成新病毒蛋白的复制的最后阶段起作用。 huSlfn11 功能的一个显着特征是选择性抑制病毒编码蛋白的合成，而宿主细胞蛋白的生产显然不受阻碍。最近，两个独立实验室利用数十种癌细胞系进行的全基因组筛选工作发现了 huSlfn11 表达与细胞对 DDA 敏感性之间有趣的相关性。使用我们在之前的研究中产生的特别缺乏 huSlfn11 的细胞系，我们发现这些细胞确实能够抵抗几类 DDA 的细胞毒性作用。因此，认为肿瘤细胞对 DDA 产生耐药性涉及 huSlfn11 的下调是相当合理的。最后，我们的最新研究表明 huSlfn 5 和 11 具有结合和/或生成 Z-DNA 的能力。由于 Z-DNA 双螺旋的结构与 B-DNA 有很大不同，因此它支持与其他分子不同的相互作用，一些蛋白质已被鉴定出选择性地与 Z-DNA 结合，但不与 B-DNA 结合。还值得注意的是，与 B-DNA 不同，Z-DNA 具有很强的免疫原性，不仅可以生产用于研究目的的高度特异性抗体，而且还可以在红斑狼疮等自身免疫性疾病中产生抗 Z-DNA 抗体。尽管左手 Z-DNA 和 Z-RNA 形式在几十年前就被发现了，但它们的生物学作用仍然是个谜，很大程度上是因为关于它们在生理条件下形成的信息很少。因此，几十年来，人们对 Z-DNA 功能的了解并不多。事实上，自 20 世纪 80 年代末以来，Z-DNA 的生物学并没有受到研究人员或资助机构的太多关注，除了少数例外，人们的注意力集中在 Z-DNA 在遗传不稳定性中的作用。我们发现 Slfns（干扰素诱导的抗病毒蛋白家族）生成 Z-D/RNA，具有将这些左手核酸置于多种免疫反应场景中的强大潜力。了解 Z-D/RNA 的生物学作用对于开发其在疫苗佐剂、抗病毒或抗肿瘤化疗药物开发中的潜在药理学可能性至关重要。