Mechanisms of meiotic and mitotic recombination

减数分裂和有丝分裂重组机制

基本信息

批准号：
10593114
负责人：
JEFF J. SEKELSKY
金额：
$ 54.48万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10593114
关键词：
Aneuploidy Biochemistry Biology CRISPR gene drive Cell Proliferation Cell division Cells Cellular biology Chromosome Segregation Chromosomes Congenital Abnormality DNA Damage DNA Double Strand Break Dangerousness Defect Double Strand Break Repair Drosophila genus Genetic Genetic Crossing Over Genetic Recombination Genomic Instability Genomics Germ Cells Investigation Laboratories Malignant Neoplasms Meiosis Meiotic Recombination Mitotic Mitotic Recombination Molecular Outcome Pattern Pregnancy loss Process Regulation Research Scientist Spontaneous abortion Sterility Time Tissues Training Trisomy career design egg experimental study gene drive system mathematical model model organism repaired segregation sperm cell tumorigenesis

Aneuploidy Biochemistry Biology CRISPR gene drive Cell Proliferation Cell division Cells Cellular biology Chromosome Segregation Chromosomes Congenital Abnormality DNA Damage DNA Double Strand Break Dangerousness Defect Double Strand Break Repair Drosophila genus Genetic Genetic Crossing Over Genetic Recombination Genomic Instability Genomics Germ Cells Investigation Laboratories Malignant Neoplasms Meiosis Meiotic Recombination Mitotic Mitotic Recombination Molecular Outcome Pattern Pregnancy loss Process Regulation Research Scientist Spontaneous abortion Sterility Time Tissues Training Trisomy career design egg experimental study gene drive system mathematical model model organism repaired segregation sperm cell tumorigenesis

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项目摘要

ABSTRACT Recombination is both a means to avoid genome instability and to process that generates genome instability. In meiosis, DNA double-strand breaks are repaired into crossovers that are essential for accurate segregation of homologous chromosomes; defects in this process result in sterility or aneuploidy, the major cause of pregnancy loss and trisomy. Conversely, in mitotically proliferating cells double-strand breaks are a dangerous class of DNA damage. Repair of breaks in this context is done without making crossovers; formation of crossovers in mitotic cells can lead to chromosome rearrangements and tumorigenesis. Research in my laboratory focuses on mechanisms that promote crossovers in meiotic cells and non- crossover outcomes of repair in mitotic cells. We have made important contributions to understand these problems for 20 years, during which time I have trained numerous scientists who are active in research and research-related careers. This proposal sketches out both continued and new directions that will drive the field forward. These include investigations of how large gaps are repaired (important for designing Cas9 fragment integration experiments and Cas9-based gene drive systems) and how meiotic crossovers are patterned (important for proper segregation of chromosomes into gametes). We use a combination of genetics, primarily using Drosophila as a model organism, genomics, biochemistry, cell biology, evolutionary biology, and mathematical modeling.

抽象的重组既是避免基因组不稳定性的一种手段，又是产生基因组不稳定性的过程。在减数分裂中，将DNA双链断裂修复到跨界时，这对于准确同源染色体的分离；此过程中的缺陷导致不育或非整倍性，主要是妊娠丧失和三体性的原因。相反，在有丝分裂的增殖细胞中，双链断裂是一个危险类DNA损伤。在这种情况下，修复休息时间是在不进行跨界的情况下完成的；有丝分裂细胞中跨界的形成会导致染色体重排和肿瘤发生。我的实验室的研究重点是促进减数分裂细胞和非 - 有丝分裂细胞修复的跨界结果。我们为理解这些做出了重要的贡献有20年的问题，在此期间，我培训了许多积极研究和的科学家与研究有关的职业。该提案勾勒出持续的和新的方向，这些方向将推动田地向前。其中包括对修复大小的修复的调查（对于设计CAS9很重要碎片集成实验和基于CAS9的基因驱动系统）以及减数分裂的交叉图案化（对于将染色体适当分离为配子的重要性很重要）。我们结合了遗传学主要使用果蝇作为模型生物，基因组学，生物化学，细胞生物学，进化生物学和数学建模。