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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（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抗措施组成。了解先天免疫反应和促进或限制感染不同步骤动力学的途径对于在这些感染性疾病过程中设计用于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的早期反应基因（ISG）发挥其抗病毒作用。这种ISG的扩展家族是Schlafen（Slfn）基因，其除了IFN之外还通过病原体与细胞接触直接诱导。在我们寻求定义Slfn蛋白的生物学功能时，我们发现huSlfn 11有效地抑制逆转录病毒（包括HIV）的产生。我们的研究表明，huSlfn 11表达对感染周期的早期阶段没有影响，但huSlfn 11蛋白在复制的晚期阶段起作用，在此阶段合成新的病毒蛋白。huSlfn 11功能的显著标志是选择性抑制病毒编码蛋白的合成，而生产宿主细胞蛋白显然不受阻碍。最近，来自两个独立实验室的全基因组筛选工作采用了数十种癌细胞系，发现huSlfn 11表达与细胞对DDA的敏感性之间存在有趣的相关性。使用我们在先前的研究中产生的特别缺乏huSlfn 11的细胞系，我们发现这些细胞确实对几类DDA的细胞毒性作用具有抗性。因此，认为肿瘤细胞对DDA的抗性的发展涉及huSlfnll的下调是相当合理的。最后，我们最新的研究表明，huSlfn 5和11具有结合和/或产生Z-DNA的能力。由于Z-DNA双螺旋的结构与B-DNA的结构有很大不同，因此它支持与其他分子的不同相互作用，并且已经鉴定出一些蛋白质选择性地结合Z-DNA而不结合B-DNA。还值得注意的是，与B-DNA不同，Z-DNA具有很强的免疫原性，这不仅允许产生用于研究目的的高度特异性抗体，而且还在自身免疫性疾病如红斑狼疮中产生抗Z-DNA抗体。虽然左手的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一个谜，主要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的功能并没有太多的了解。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，Z-DNA在遗传不稳定性中的作用。我们发现的Z-D/RNA产生的Slfns，干扰素诱导的抗病毒蛋白质家族，有很强的潜力，将这些左手核酸到许多免疫反应的情况。了解Z-D/RNA的生物学作用是开发其在疫苗佐剂、抗病毒或抗肿瘤化疗药物中的潜在药理学可能性的基础。