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：
10248457
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 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10248457
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.

项目概要我们提出了一种跨物种的方法来了解维持细菌基因组完整性的途径细胞。物种的延续需要保护基因组免受内源和外源的影响威胁。这一点在生殖细胞（卵子和精子的前身）中最为重要。缺陷在警惕途径导致基因组完整性丧失以及随后后代活力的恶化和/或流产。对新发现的高度保守遗传因子 GCNA（生殖细胞核）的详细研究酸性肽酶）将为基因组完整性和生育力的关键决定因素提供新的见解。我们的初步数据表明，GCNA 的丢失会导致果蝇和秀丽隐杆线虫的基因组不稳定，表明功能守恒。这里概述的实验将提供一些初步的见解保守的GCNA家族成员促进基因组完整性和生育力的共享机制物种。我们发现 GCNA 与拓扑异构酶 2 相互作用并阻止 DNA:蛋白质的形成交联（DPC）。 GCNA突变动物表现出染色体丢失增加、突变积累增加，细胞周期缺陷，使 GCNA 处于多个基因组完整性过程的中心。探索为了了解 gcna 在生殖细胞维持中发挥作用的机制，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对细胞周期调节的贡献，2) 表征与拓扑异构酶 2 的相互作用，识别保守的结合伴侣，并阐明 DPC 的性质和病因学，以及 3) 了解 GCNA 的域结构及其功能相关性对人类的生育能力。