Tudor Domain Proteins in Germline Genome Defense

种系基因组防御中的 Tudor 结构域蛋白

• 批准号: 10614966
• 负责人: Chen Chen
• 金额: $ 32.28万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10614966
• 关键词: Affinity; Animals; Area; Bacteria; Binding; Binding Proteins; Biochemical; Biogenesis; Biology; Cells; DNA Damage; DNA Transposable Elements; Data; Defense Mechanisms; Development; Developmental Biology; Drosophila genus; Family; Fertility; G-Quartets; Gametogenesis; Genetic Transcription; Genome; Genomics; Germ Cells; Immune system; Individual; Infertility; Knowledge; Male Infertility; Meiosis; Mus; Mutation; N-terminal; Parasites; Pathway interactions; Phase; Plants; Play; Production; Property; Proteins; RNA; RNA Binding; RNA Helicase; RNA-Binding Proteins; RNA-Protein Interaction; Regulation; Reporting; Research; Role; Small RNA; Spermatocytes; Spermatogenesis; Structure; Subgroup; Tertiary Protein Structure; Testing; Transcriptional Silencer Elements; fetal; genetic information; genome integrity; helicase; insight; male fertility; mouse model; next generation; novel; piRNA; sperm cell

PROJECT SUMMARY Transposable elements (TEs) are “genomic parasites” that can replicate and re-integrate into the host cell genome. Uncontrolled TE activity in germ cells leads to DNA damage, disruption of gametogenesis, and infertility. In mammalian male germ cells, the PIWI- piRNA pathway uses small RNAs as a guide to silence mobile TEs to protect genome integrity and sustain fertility. The proper production of piRNAs is critical for TE silencing and spermatogenesis. However, the mechanisms governing piRNA biogenesis are not well understood. In particular, the roles of many RNA binding proteins during piRNA biogenesis remain elusive. By studying a subgroup of Tudor domain proteins that also harbor LOTUS domains, we discovered that TDRD5 is a novel RNA binding protein critical for piRNA biogenesis in mice. Strikingly, we have discovered a novel RNA binding property of LOTUS domains that is conserved in bacteria, plants and animals. This binding property is different from reported protein binding feature of some animal LOTUS domains. We hypothesize that animal LOTUS domains have both RNA and protein binding activities and that the LOTUS group of Tudor domain proteins together play critical roles in mammalian piRNA biogenesis. To test this hypothesis, we will use biochemical approaches and mouse models to: 1) Clarify the RNA and protein binding activities of the LOTUS domain superfamily; 2) Determine the mechanism of a specific LOTUS domain-RNA interaction; and 3) Define the functional involvement of LOTUS domain proteins in piRNA biogenesis and Vasa regulation in mice. These studies will provide valuable new insights into the mechanisms of piRNA biogenesis that safeguard germline genome integrity to sustain male fertility and expand our knowledge in broader RNA biology and developmental biology.

项目总结