At a Glance
Studies have implicated the failure of proper chromosome segregation, a process that is critical for cell proliferation and for maintaining life in all organisms, in both cancer and birth defects. This project explored the scientific premise that the kinetochore, a protein structure that forms during cell division, ensures proper chromosome segregation and prevents errors in mitosis.
This project provided fundamental insights into cancer and developmental diseases by yielding new understanding of kinetochore functions. Through the work completed during this grant period, the researchers were able to make progress on developing a novel super-resolution imaging methodology which is not only well-suited to studying kinetochore dysfunction, but also can be utilized for broad research fields.
The Challenge
Accurate chromosome segregation during mitosis is necessary for maintaining the production of cells and preventing cancer. In order to achieve accurate chromosome segregation, microtubules must properly bind to kinetochores, which is a protein complex assembled at a specific site on the chromosome, the centromere. The physical size of a kinetochore is 200 nm and smaller than resolutions of light microscopy, which poses significant challenges when studying their functions. Thus, additional research is needed to mechanistically explain how human kinetochores couple force for accurate chromosome segregation.
Project Goals
The goal of this project was to discover mechanisms at the molecular level that ensures the integrity of chromosome segregation. The researchers used three aims to guide their research into new understanding of kinetochore functions and thus provided fundamental insights into cancer and developmental diseases.
Results
Although the work in this project is still ongoing, this study provided fundamental insights into cancer and developmental diseases by yielding new understanding of kinetochore functions. The work done on this project will result in the development of refined protocols and techniques. As of the conclusion of this grant, project staff was able to make progress on developing new biosensors, and novel protocols in super-resolution microscopy which are well-suited to studying kinetochore dysfunction. Many studies suggest that kinetochore dysfunctions lead to aneuploidy, chromosomal instability, carcinogenesis, and patient poor outcomes from cancer chemotherapy, although these mechanisms require further research.
This work led to new collaborations and partnership to achieve the specific goals and objectives. These partnerships include Dr. Yuta Shimamoto (National Institute of Genetics, Japan) and Dr. Mark Burkard (Department of Medicine, UW–Madison).
Looking to the Future
The research team’s long-term goals focus on discovering mechanistically how the loss of kinetochore integrity causes chromosome instability and developmental defects, with the ultimate goal of providing novel therapeutic strategies for clinical cancer therapy and preventing birth defects.
Lasting Impact
The research team is developing innovative toolkits, including a tension biosensor and a super-resolution microscopy method, to understand the function of kinetochores in organizing accurate movements of chromosomes. In future work with human cells, this tension biosensor will be useful for better understanding of kinetochore functions. The researchers’ novel 12-fold mExM, super-resolution microscopy also provides an economical alternative of existing expensive super-resolution microscopes. These results will promote and support projects in various research fields.