Chromosome breakage, pairing and replication: impacts on cell fate and function

染色体断裂、配对和复制：对细胞命运和功能的影响

• 批准号: 10388397
• 负责人: KENT G GOLIC
• 金额: $ 38.13万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-20 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10388397
• 关键词: Affect; Aneuploidy; Area; Cancerous; Cell Nucleus; Cell physiology; Cells; Centromere; Chromosomal Breaks; Chromosome Breakage; Chromosome Pairing; Chromosome Structures; Chromosomes; DNA Replication Timing; DNA biosynthesis; Dicentric chromosome; Drosophila melanogaster; Euchromatin; Eukaryota; Failure; Frequencies; Gene Expression; Genes; Genetic Diseases; Genetic Materials; Genetic Recombination; Genome; Genome Stability; Germ Cells; Health; Heterochromatin; Histones; Human; Investigation; Lead; Maintenance; Malignant Neoplasms; Meiosis; Mitotic Chromosome; Modeling; Mutation; Pattern; Proteins; Site; Testing; Variant; Work; Yeasts; cancer cell; chromosome replication; daughter cell; experimental study; male; prevent; repaired

Project Summary This proposal describes investigations in three main areas to understand how the organization of chromosomes in the nucleus, and their differentiation into heterochromatin and euchromatin, impacts chromosome breakage and repair, chromosome pairing, and chromosome replication in Drosophila melanogaster. In the first part, dicentric chromosomes are generated in the male germline, where they typically break, delivering a chromosome with a broken end to each daughter cell. The influence of structurally distinct centromeres and the amount of centromeric histone CenpA on the fate of these chromosomes will be examined. Experiments will be undertaken to understand how cells with a broken chromosome choose their fate, to repair or to die, and how they choose between different modes of repair. These choices have obvious relevance for human health. When a cell lives, but fails to repair damage, it may become cancerous. The mode of repair can determine whether gametes transmit a normal genome, or a genome with deficiencies or other structural variants or mutations. One particular mode of repair, Break Induced Replication, is known to be mutagenic in yeast, and has been implicated in chromosome change in humans. Chromosomes repaired by BIR will be examined to determine the types and frequencies of mutations produced in the germline of a higher eukaryote. In the second part of this work, the mechanism of mitotic chromosome pairing will be examined. Significant progress has been made in identifying genes that promote or inhibit pairing, but how homologous regions of chromosomes find each other to initiate pairing is still a mystery. This work will test various models for the initiation of pairing by studying the frequency of site-specific recombination within and between rearranged chromosomes. This work also has human health relevance, since failures of meiotic pairing can lead to gametes with chromosomal aneuploidy. Some cancer cells also show inappropriate homologous pairing, implying a possible connection between these chromosome and cellular states. In the third part of the proposed work, the timing of DNA replication in heterochromatin will be examined. Mutations in genes that encode proteins that affect heterochromatin will be tested to determine their effects on replication timing. Proper maintenance of heterochromatin is important for genome stability, and disruption of its normal pattern of replication can lead to altered gene expression, with impacts on cellular function and health.

项目摘要 该建议描述了在三个主要领域的调查，以了解组织的组织 细胞核中的染色体及其分化为异染色质和白染色质，会影响 果蝇中的染色体破裂和修复，染色体配对和染色体复制 Melanogaster。在第一部分中，在男性种系中产生二含染色体，通常在那里 打破，输送一个染色体，每个女儿细胞都折断了末端。结构上不同的影响 将检查这些染色体命运上的丝粒和丝粒组蛋白CENPA的量。 将进行实验，以了解染色体破裂的细胞如何选择其命运，以修复 或死亡，以及它们如何在不同的维修模式之间进行选择。这些选择与 人类健康。当细胞生存但无法修复损害时，它可能会变成癌。维修方式可以 确定配子是否传递正常基因组，还是具有缺陷或其他结构变体的基因组 或突变。一种特定的维修方式，即破裂引起的复制，已知在酵母中是诱变的，并且 与人类的染色体变化有关。 BIR修复的染色体将检查到 确定较高真核生物种系中产生的突变的类型和频率。 在这项工作的第二部分中，将检查有丝分裂染色体配对的机制。 在识别促进或抑制配对的基因方面取得了重大进展，但如何同源 染色体区域相互发现以启动配对仍然是一个谜。这项工作将测试各种模型 通过研究内部和重新排列的位点特异性重组的频率来启动配对 染色体。这项工作也具有人类健康的相关性，因为减数分裂配对的失败会导致配子 与染色体非整倍性。一些癌细胞还显示出不适当的同源配对，这意味着 这些染色体和细胞状态之间的可能联系。 在拟议的工作的第三部分中，将检查异染色质中DNA复制的时机。 将测试影响异染色质的蛋白质的基因突变，以确定其对其对 复制时机。正确维持异染色质对于基因组稳定性很重要，及其破坏 正常的复制模式会导致基因表达改变，并对细胞功能和健康产生影响。