Viral Noncoding RNAs and Cell Transformation

病毒非编码 RNA 和细胞转化

• 批准号: 10553131
• 负责人: JOAN A. STEITZ
• 金额: $ 67.28万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-20 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10553131
• 关键词: 2019-nCoV; 3' Untranslated Regions; Adopted; B-Lymphocytes; Binding; Biogenesis; Biological; Callithrix; Cancer Patient; Cebidae; Cell Nucleus; Cell physiology; Cells; Collaborations; Coronavirus; Cytoplasm; DNA biosynthesis; Databases; Diagnostic; Elements; Epstein-Barr virus encoded RNA 2; Evolution; Gene Expression; Genome; Goals; Herpesviridae; Human; Human Herpesvirus 4; Human Herpesvirus 8; Immune response; Immune signaling; Immunocompromised Host; In Vitro; Individual; Infection; Infectious Agent; Infectious Mononucleosis; Investigation; Lymphoid Cell; Lymphoma; Lytic; Lytic Phase; Malignant Neoplasms; Mass Spectrum Analysis; Measurement; Messenger RNA; MicroRNAs; Molecular; Monkeys; Mutagenesis; Nuclear; Nuclear Export; Oncogenic; Poly A; Polyadenylation; Population; Primates; Process; Production; Protein Biosynthesis; Protein Engineering; Proteins; Proteome; RNA; RNA Databases; RNA Sequences; RNA Stability; RNA-Binding Proteins; Resolution; Ribonucleoproteins; Roentgen Rays; Role; SARS-CoV-2 genome; SARS-CoV-2 infection; Saimiriine Herpesvirus 2; Shapes; Signal Transduction; Small RNA; Structure; System; T-Lymphocyte; Tail; Testing; Therapeutic; Transcript; Untranslated RNA; Viral; Viral Proteins; Virion; Virus; cell growth; cell growth regulation; cell transformation; combat; crosslink; design; differential expression; expectation; gene function; insight; leukemia/lymphoma; mRNA Export; messenger ribonucleoprotein; mutant; novel; sarcoma; transcriptome; transforming virus; triple helix; viral DNA; viral rescue

Project Summary/Abstract The roles of noncoding (nc)RNAs in lymphoid cells harboring each of three oncogenic herpesviruses are being investigated. Epstein-Barr virus (EBV) infects and transforms human B cells; it is the causative agent of infectious mononucleosis and is associated with several human cancers. Herpesvirus saimiri (HVS) induces fatal lymphomas and leukemias in New World monkeys and transforms human T lymphocytes in culture. Kaposi's sarcoma-associated herpesvirus (KSHV) afflicts immunocompromised individuals and persists in a latent form until lytic activation. In recent years, we have focused our efforts on the structure and functions of the two EBV-encoded EBERs, the seven HVS-encoded HSURs and six HVS microRNAs, as well as the KSHV PAN RNA. These viral ncRNAs are all abundant, conserved between related viruses and bind host proteins to form ncRNPs. Our functional studies have uncovered novel mechanisms of microRNA biogenesis and decay, revealed that viral ncRNPs can be essential for nuclear processes as diverse as viral DNA replication (EBER2) or mRNA export to the cytoplasm (PAN), identified the role of triple helices in RNA stabilization, and contributed important insights into viral evolution. Most compelling is that our studies of viral ncRNAs have uncovered the existence of and begun to elucidate novel cellular mechanisms such as the regulation of cellular microRNA populations and how the polyA tail and 3′UTR may collaborate to stabilize cellular mRNAs. Proposed aims will exploit these advances to further investigate the underlying molecular mechanisms. We shall extend our original discovery of target-directed microRNA decay (TDMD) to identify proteins and additional RNA signals contributing to cellular microRNA degradation, as well as investigate the role of a putative small RNA derived from the SARS-CoV-2 genome in regulating host immune responses, with potential diagnostic/therapeutic implications. We shall establish how its polyA tail as well as internal sequences contribute to PAN RNA's ability to enable the nuclear export of late lytic mRNAs, leading to virion protein production and virion release. We shall search cellular transcriptome databases for the presence of RNA sequence/structure motifs contributing to polyA-3′UTR interactions (and presumably RNA stabilization), as recently revealed by our high-resolution X-ray analyses. Newly discovered triplex-forming elements (ENEs) in coronavirus RNAs will be analyzed for their stabilization activity and possible contributions to viral protein synthesis, with potential therapeutic applications. Extensive interactions between viral transcripts in EBV- infected cells discovered by psoralen crosslinking will be validated and further analyzed.

项目总结/文摘