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Centromere Function and Dicentric Chromosome Stability

着丝粒功能和双着丝粒染色体稳定性

基本信息

批准号：
10016344
负责人：
BETH A SULLIVAN
金额：
$ 32.2万
依托单位：
DUKE UNIVERSITY
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：
2019-09-11 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10016344
关键词：
Affect Aneuploidy Animal Model Architecture Area Behavior Binding Biological Biological Assay Biological Models Biology Cell Cycle Cell Death Cell division Cells Centromere Chromosomal Stability Chromosome Segregation Chromosome Structures Chromosome abnormality Chromosomes Congenital Abnormality Cytology DNA Damage Data Diagnosis Dicentric chromosome Distant Engineering Ensure Epigenetic Process Event Frequencies Genetic Genetic Transcription Genome Genome Stability Genomic Instability Genomics Goals Human Human Chromosomes Individual Infertility Investigation Isochromosomes Karyotype Kinetochores Knowledge Label Lead Link Maize Malignant Neoplasms Measures Meiosis Microtubules Mitotic Modeling Modification Molecular Molecular Structure Outcome Patients Pattern Population Protein Dynamics Proteins Publishing Reagent Research Role Satellite DNA Series Sister Stress Structure System Testing Time TimeLine Transcript Untranslated RNA Work base chromosome movement chromosome number abnormality experience human disease insight novel offspring reproductive segregation structural genomics tool transmission process tumorigenesis

项目摘要

Chromosome inheritance ensures transmission of genetic and genomic information. Abnormal chromosome number (aneuploidy) and altered chromosome structure cause birth defects, reproductive abnormalities, and cancer. The centromere is the locus required for chromosome segregation and genome stability. Normal chromosomes typically have only one centromere, but, genome rearrangements associated with birth defects and cancer produce chromosomes in which two centromeres are physically linked. These dicentrics are not usually tolerated in most model organisms, as originally illustrated in maize by Barbara McClintock nearly 80 years ago. Paradoxically, dicentric chromosomes occur frequently in the general human population and are extremely stable during cell division. A major impediment in studying dicentric chromosome formation and fate in humans has been the absence of experimental systems. To circumvent this long-standing problem, we developed assays to experimentally create dicentric human chromosomes that molecularly mirror those that occur naturally and are biomedically relevant. We showed that in some of these de novo dicentrics, centromere inactivation occurred by partial centromere deletion. However, many of our engineered dicentric chromosomes, particularly dicentric X isochromosomes (dicXs), retain two active centromeres and are very stable. This finding appears to contradict McClintock's model of dicentric fate. In this proposal, we will build on our previous studies of dicentric human chromosomes by leveraging an inducible dicX assay system to explore molecular mechanisms governing stability of dicXs that maintain two active centromeres. We will focus on three major areas of investigation: 1) defining the molecular links between dicentric structure (i.e. inter-centromere distance) and centromere composition and kinetochore architecture; 2) testing the roles of alpha satellite genomic structure and transcription in dicentric stability, and 3) investigating mechanisms of centromere protein inheritance that result in varying centromere configurations on dicXs. Our work will place specific genomic and epigenetics events on the timeline of dicentric formation and stabilization by making use of a powerful chromosome engineering system that generates dicentric chromosomes that precisely model those that occur frequently in humans. These studies will also be critical for understanding dicentric formation and structure, refining long-established models of dicentric stability, and providing new molecular insights into inheritance of centromere function in humans.

染色体遗传确保遗传和基因组信息的传递。染色体异常