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Mechanisms to move and steer chromosomes

移动和操纵染色体的机制

基本信息

批准号：
9750300
负责人：
P. TODD STUKENBERG
金额：
$ 32.3万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9750300
关键词：
Actins Address Anaphase Bacteria Behavior Binding Biological Assay CENP-E protein Cell division Cells Cellular biology Chromatids Chromosomes Complex Coupled Development Drug Targeting Ensure Eukaryota Event Family Feedback Fluorescence Resonance Energy Transfer Future Generations Genetic Materials Genomic Instability Gout Harvest Human Human Chromosomes In Vitro Kinesin Kinetochores Ligation Malignant Neoplasms Measures Mechanics Metaphase Metaphase Plate Methods Microtubule Depolymerization Microtubule Polymerization Microtubules Mitosis Mitotic spindle Modeling Motor Movement Names Nature Pathway interactions Pharmaceutical Preparations Phosphorylation Plasmids Plus End of the Microtubule Polymers Power stroke Process Prometaphase Proteins Regulatory Pathway Relapse Signal Transduction Sister Slide Structure System Testing Therapeutic Tubulin Vinca Alkaloids Work Yeasts arm calponin cancer cell chemotherapy chromosome movement depolymerization dimer experimental study foot fungus in vivo mutant polymerization segregation single molecule taxane tomography

项目摘要

Project Summary/Abstract We will elucidate the mechanisms that power the movements of chromosomes on the mitotic spindle and the mechanisms that control the direction of these movements. Fungi use the ring shaped Dam1 complex, which works with multiple “arm-like” Ndc80 complexes to move chromosomes. This ring can be pushed poleward by a “power stroke” generated when depolymerizing microtubules curve at the plus end to power the movement of chromosomes. However, it is unclear how most eukaryotes, including humans, power chromosome movement since they lack the Dam1 ring complex. We visualized purified human Ndc80 and Ska complexes on microtubules by EM tomography to elucidate the structure of the human kinetochore-microtubule attachment. These new structures orient Ska on microtubules and also suggest Ndc80 complexes oligomerize on microtubules to form a structure we have named the “sliding foot”. This new structure suggests testable mechanisms for how metazoans kinetochores are pushed by the curvature of a depolymerizing microtubule like yeast. We have developed two in vivo assays that allow us to measure the formation of the sliding feet and to measure the chromosome movements that require Ska. In addition, we will employ single molecule assays to measure the requirement of the sliding foot to generate force in vitro. Using these new assays, we will identify the mechanism that powers the movements of human chromosomes on the mitotic spindle. Surprisingly, on most chromosomes only one of the two sister kinetochores has sliding feet. This is exciting because chromosome movements require one sister to actively engage depolymerizing ~20 microtubules to pull chromosomes, while its sister must passively attach to growing microtubules. We will identify the regulatory pathways that generate the asymmetry of sliding foot formation on the two sister kinetochores. We hypothesize that these pathways not only regulate sliding foot formation but can also ensure that one sister has depolymerizing microtubules while the microtubules bound to its sister kinetochore are polymerizing. We will build on these findings to identify the mechanisms that direct chromosome movements either towards or away from poles on the mitotic spindle. It is important to understand these basic mechanisms that lie at the center of the chromatid segregation to determine how cancer cells lower the fidelity of mitosis to generate genomic instability and to increase the efficacy of anti-tubulin chemotherapeutics.

项目总结/文摘