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Programmed DNA Elimination in Parasitic Nematodes

寄生线虫中的程序性 DNA 消除

基本信息

批准号：
10269025
负责人：
Jianbin Wang
金额：
$ 51.68万
依托单位：
UNIVERSITY OF TENNESSEE KNOXVILLE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-23 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10269025
关键词：
3-Dimensional Architecture Area Ascaris Biological Biological Process Cell Cycle Cell Lineage Centromere Cessation of life Child Chromatin Chromosomal Breaks Chromosome Breakage Chromosome Structures Chromosomes Complex DNA DNA Double Strand Break DNA Replication Timing DNA biosynthesis Deposition Development Disease Drug Targeting Ensure Epigenetic Process Event Evolution Excision Exhibits Family suidae Future Generations Gene Expression Regulation Gene Silencing Generations Genes Genetic Transcription Genome Genomic Segment Genomics Health Human Invertebrates Kinetochores Lead Location Longevity Maintenance Manuscripts Maps Mitosis Molecular Molecular Biology Morbidity - disease rate Nuclear Nucleotides Organism Parasitic nematode Physiological Processes Positioning Attribute Preparation Process Public Health RNA Research Resected Site Somatic Cell Specific qualifier value Stress Structure System Testis Toxocara Toxocariasis United States Variant Vertebrates Work chromosomal location ds-DNA flexibility genetic information genome integrity genome-wide healing improved insight new therapeutic target novel recruit repaired replication stress segregation socioeconomic development telomere tool

项目摘要

Project Summary/Abstract Ascaris remains a significant health problem in many parts of the world, infecting close to a billion people, many of them children, leading to significant morbidity. The related parasitic nematode Toxocara, causing human toxocariasis, also is increasingly being recognized as a significant public health problem in the United States. These parasitic nematodes undergo a novel form of genome re-organization, known as programmed DNA elimination. Very little is known regarding the function and molecular mechanisms of this DNA elimination process. Our recent work provides fundamental insights into this process demonstrating that DNA elimination is a conserved process in a group of parasitic nematodes serving to silence germline-expressed genes, particularly testis-specific genes, through their elimination in the somatic cells. Furthermore, we defined how holocentric chromosomes are dynamically re-organized to determine chromosomes regions that will be kept or eliminated. During Ascaris DNA elimination, DNA double-strand breaks are required to generate chromosomal fragments that will be eliminated. We identified 72 telomere addition sites where the presumed chromosomal breaks occur. These sites exhibit high fidelity in different somatic cell lineages and worms constrained within 3- 6 kb genomic regions and are called chromosomal breakage regions. Our analysis did not identify any specific sequence, structural features or common epigenetic factors that might specify or recruit molecular machinery to these regions. However, a prominent feature for these break regions is they become more chromatin accessible just before DNA elimination. Open chromatin is often a result of molecular processes that access the genome, including DNA replication and RNA transcription. In this proposal, we hypothesize that RNA transcription, R-loops, and/or DNA replication stress, as well as the three-dimensional genome organization may contribute to the key DNA breaks that initiate DNA elimination. We will examine these hypotheses in three specific aims: (1). Define when DNA break and telomere addition occurs during the cell cycle that leads to a DNA elimination mitosis; (2). Define DNA replication timing and stress, RNA transcription, and R-loops during DNA elimination; and (3). Map the 3D genome organization of the break regions. In addition to an understanding of the molecular mechanisms of the DNA breaks for Ascaris DNA elimination, the proposed studies will provide new information and insights into parasitic nematode chromosomes and chromatin organization, RNA transcription, DNA replication, DNA breaks and end resection, and telomere healing. Insights into these biological processes may identify novel molecular processes that could be potential drug targets in parasitic nematodes.

项目总结/文摘