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Role of GCNA in preserving genome integrity and fertility

GCNA 在保持基因组完整性和生育力方面的作用

基本信息

批准号：
10478296
负责人：
Michael Buszczak
金额：
$ 45.27万
依托单位：
MAGEE-WOMEN'S RES INST AND FOUNDATION
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-16 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10478296
关键词：
Alleles Aneuploidy Animals Back Binding Biochemical Biochemical Genetics Caenorhabditis elegans Cell Cycle Cell Cycle Progression Cell Cycle Regulation Cell Maintenance Cell Nucleus Cell division Cell physiology Cellular biology Chemicals Chromatin Chromatin Structure Chromosome Segregation Chromosomes Congenital Abnormality DNA Damage DNA Double Strand Break DNA Repair DNA analysis DNA lesion DNA-protein crosslink Data Defect Deterioration Development Drosophila genus Embryo Embryonic Development Ensure Etiology Face Failure Family member Fertility Fostering Gametogenesis Generations Genes Genetic Genetic Materials Genome Genome Stability Genomic Instability Germ Cells Germ Lines Germ cell tumor Goals Human Image Immunoprecipitation In Vitro Infertility Lead Length Male Infertility Malignant Neoplasms Meiosis Microsatellite Instability Microsatellite Repeats Mutation Mutation Analysis Nature Nuclear Organism Pathway interactions Patients Peptide Hydrolases Phenotype Process Protein Region Proteins RNA Repetitive Sequence Research Role Source Spontaneous abortion Sterility Structure Topoisomerase Totipotency Touch sensation Transgenes Work Zebrafish chromosome loss egg experimental study fly genetic approach genome integrity genome wide association study human male in vivo insight mutant novel offspring preservation prevent programs protein function sperm cell transmission process vigilance

项目摘要

PROJECT SUMMARY We propose a cross-species approach to understand the pathways that maintain genome integrity in germ cells. The perpetuation of the species requires that the genome is protected from endogenous and exogenous threats. Nowhere is this more critical than in the germ cells, the precursors of egg and sperm. Defects in the vigilance pathways lead to loss of genome integrity and subsequent deterioration of offspring vigor and/or miscarriage. Detailed studies of a newly identified, highly conserved genetic factor, GCNA (Germ Cell Nuclear Acidic Peptidase), will provide novel insights into key determinants of genome integrity and fertility. Our preliminary data show that loss of GCNA results genomic instability in both Drosophila and C. elegans, indicating conservation of function. The experiments outlined here will provide some of the first insights into the shared mechanisms by which conserved GCNA family members promote genomic integrity and fertility across species. We find that GCNA both interacts with Topoisomerase 2 and prevents the formation of DNA:protein crosslinks (DPCs). GCNA mutant animals display increased chromosome loss, mutation accumulation, and cell cycle defects, placing GCNA at the hub of multiple genome integrity processes. To explore the mechanisms underlying gcna functions in germ cell maintenance, we propose three specific aims: 1) to analyze the etiology of chromosome loss, and to determine the contribution of gcna to cell cycle regulation, 2) to characterize the interaction with topoisomerase 2, identify conserved binding partners, and illuminate the nature and etiology of DPCs, and 3) to understand the domain structure of GCNA and its functional relevance to human fertility.

项目摘要我们提出了一种跨物种的方法来了解维持基因组完整性的途径，细胞物种的延续需要基因组受到保护，不受内源性和外源性的影响。威胁这一点在生殖细胞（卵子和精子的前体）中最为关键。缺陷警惕途径导致基因组完整性丧失和后代活力的随后恶化，和/或流产一种新发现的高度保守的遗传因子GCNA（生殖细胞核因子）的详细研究酸性肽酶），将提供新的见解基因组完整性和生育力的关键决定因素。我们初步数据显示GCNA的缺失导致果蝇和C.优雅，表明功能的保守性。这里概述的实验将提供一些初步的见解保守的GCNA家族成员通过共同的机制促进基因组的完整性和生育力。物种我们发现GCNA既与拓扑异构酶2相互作用，又阻止DNA：蛋白质的形成。交联（DPC）。GCNA突变动物表现出增加的染色体丢失、突变积累，细胞周期缺陷，将GCNA置于多个基因组完整性过程的中心。探讨 gcna在生殖细胞维持中的功能机制，我们提出了三个具体目标：1）分析染色体丢失的病因，并确定gcna对细胞周期调控的贡献，2）表征与拓扑异构酶2的相互作用，鉴定保守的结合伴侣，并阐明 DPC的性质和病因学，以及3）了解GCNA的结构域及其功能相关性对人类生育能力的影响