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.

翻译后摘要：虽然通过减数分裂产生的精子和卵子是精致的协调和严格的监管， 染色体分离非常容易出错。在人类中，据估计约5%的精子和约30%的 卵母细胞具有错误的染色体互补--称为非整倍性。因此，减数分裂错误 染色体分离是导致精神残疾、流产和不育的主要原因。在哺乳动物中， 确保染色体可靠分离的关键步骤包括产生程序化的DNA双链， PRDM 9热点处的双链断裂（DSB），其富含双组蛋白H3赖氨酸4和赖氨酸36 三甲基化（K4/H3 K36 me 3），亲本染色体（同源物）的配对，同源物的共对齐 纵向，和同源物的拴系通过交叉-染色体臂之间的交换 同系物。尽管知识丰富，但这一过程中的一个关键知识差距是， 双重H3 K4/H3 K36 me 3修饰影响同源物配对和重组。我们和其他人已经证明 ZCWPW 1是一种双重组蛋白甲基化阅读器，在PRDM 9靶位点富集，对PRDM 9的数量没有影响。 或DSB的位置，但可能对DSB修复很重要。更具体地说，我们的初步数据表明， ZCWPW 1可能是有效的同源配对所必需的，当受损时，在染色体中达到高潮 缠结，DSB修复缺陷，最终染色体错误分离和不育。所以我们 建议使用遗传学、基因组学、分子学和生物化学进行全面和综合的分析 方法来剖析ZCWPW 1在同源配对和重组中的作用。总的来说，这些研究将 提供有关减数分裂染色体动力学的基础知识和对染色体的机械理解。 ZCWPW 1在哺乳动物减数分裂中的作用。