The role of ZCWPW1 in meiosis

ZCWPW1 在减数分裂中的作用

• 批准号: 10680189
• 负责人: Francesca Cole
• 金额: $ 63.4万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10680189
• 关键词: Address; Affect; Aneuploidy; Binding; Biochemical; Bypass; Cell Cycle; Characteristics; Chromosome Arm; Chromosome Pairing; Chromosome Segregation; Chromosome abnormality; Chromosomes; Compensation; Constitution; Constitutional; Cytology; DNA Double Strand Break; DNA Repair; Data; Defect; Diploidy; Double Strand Break Repair; Down Syndrome; Ensure; Etiology; Event; Failure; Female; Frequencies; Functional disorder; Generations; Genetic; Genetic Crossing Over; Genetic Recombination; Genome; Genomic Segment; Genomics; Genotype; Germ Cells; Haploidy; Histone H3; Histones; Homologous Gene; Human; Hybrids; Immunoprecipitation; In Vitro; Infertility; Knowledge; Lead; Location; Lysine; Male Infertility; Mammals; Mass Spectrum Analysis; Mediating; Meiosis; Meiotic Prophase I; Meiotic Recombination; Methylation; Methyltransferase; Modeling; Modification; Molecular; Monitor; Mus; Nuclear Envelope; Nuclear Inner Membrane; Oocytes; Play; Ploidies; Process; Production; Prophase; Proteins; Psyche structure; Reader; Role; SPO11 gene; Site; Speed; Spermatocytes; Spontaneous abortion; System; Testing; Time; biophysical properties; chromosome missegregation; chromosome movement; disability; egg; experimental study; genetic approach; genetic information; high resolution imaging; histone methylation; in vivo; insight; male; mutant; sex; sperm cell; telomere

Abstract: While generation of sperm and eggs through meiosis is exquisitely coordinated and tightly regulated, chromosome segregation is remarkably error prone. In humans it is estimated that ~5% of sperm and ~30% of oocytes have the wrong chromosome complement - known as aneuploidy. As such, errors in meiotic chromosome segregation are a leading cause of mental disability, miscarriage, and infertility. In mammals, critical steps that ensure faithful chromosome segregation include generation of programmed DNA double- stranded breaks (DSBs) at PRDM9 hotspots that are enriched for dual Histone H3 lysine 4 and lysine 36 trimethylation (K4/H3K36me3), the pairing of parental chromosomes (homologs), the co-alignment of homologs lengthwise, and the tethering of homologs by crossing over – the exchange of chromosome arms between homologs. Despite this wealth in knowledge, a key gap in knowledge in this process is how PRDM9-dependent dual H3K4/H3K36me3 modifications influence homolog pairing and recombination. We and others have shown that ZCWPW1, a dual histone methylation reader, is enriched at PRDM9 target sites, has no effect on the number or location of DSBs, but may be important for DSB repair. More specifically, our preliminary data suggest that ZCWPW1 may be required for efficient homolog pairing which when compromised culminates in chromosome entanglements, DSB repair defects, and ultimately chromosome mis-segregation and infertility. Therefore, we propose a comprehensive and integrative analysis using genetic, genomic, molecular, and biochemical approaches to dissect the role of ZCWPW1 in homolog pairing and recombination. Overall, these studies will provide fundamental knowledge about meiotic chromosome dynamics and a mechanistic understanding of the role of ZCWPW1 in mammalian meiosis.

摘要：虽然通过减数分裂的生成精子和卵的产生完全协调并受到严格调节，但 染色体分离非常容易出错。在人类中，估计约有5％的精子和约30％ 卵母细胞的染色体完成错误 - 被称为非整倍性。因此，减数分裂的错误 染色体分离是精神残疾，流产和不育症的主要原因。在哺乳动物中， 确保忠实染色体隔离的关键步骤包括生成编程的DNA双重 在富含双重组蛋白H3赖氨酸4和赖氨酸36的PRDM9热点处的滞留断裂（DSB） 三甲基化（K4/H3K36me3），父母染色体的配对（同源物），同源物的共对象 纵向，以及通过越过的同源物的束缚 - 在之间的染色体臂之间的交换 同源物。尽管知识中有这些财富，但在此过程中，Knowle的关键差距是PRDM9依赖性的 双H3K4/H3K36ME3修改会影响同源配对和重组。我们和其他人已经表明 ZCWPW1是一种双重组蛋白甲基化读取器，在PRDM9目标位点富集，对数量没有影响 或DSB的位置，但对于DSB维修可能很重要。更具体地说，我们的初步数据表明 有效的同源配对可能需要ZCWPW1，而当损害在染色体中的高潮时 纠缠，DSB修复缺陷以及最终的染色体错误分离和不育。因此，我们 建议使用遗传，基因组，分子和生化的全面和综合分析 剖析ZCWPW1在同源配对和重组中的作用的方法。总体而言，这些研究将 提供有关减数分裂染色体动力学的基本知识以及对 ZCWPW1在哺乳动物减数分裂中的作用。