The Role of Kinetochore-Microtubule Functions in Cancer-Initiating Chromosomal Missegregation
Advisor(s)
Dr. Dileep Varma; Northwestern University, Feinberg School of Medicine
Discipline
Medical and Health Sciences
Start Date
21-4-2021 10:25 AM
End Date
21-4-2021 10:40 AM
Abstract
Over the past few decades, one of the largest improvements in cancer therapeutic agents has been the use of mitotic poisons. However, as substantially effective as they are, mitotic poisons’ non-selective involvement in other pivotal physiologic processes entail the necessity of carrying out perturbations to novel components that are explicit to the cell cycle/division pathway. Chromosomal abnormalities, known as aneuploidy, is due to a deterioration of mitotic fidelity resulting in chromosomal instability (CIN): a hallmark of cancer. The primary defect behind these abnormalities are improper kinetochore-microtubule (kMT) attachments and the dysfunction of the proteins involved in this process. Therefore, the underlying biological and mechanistic nuances of kMT attachments in mitosis serve as an appealing therapeutic target in light of their central role in accurate, proportionate chromosome segregation. We find that kinetochore/centromere structure and distribution is impeded when the nuclear envelope function is compromised. We computed the centromere intensity and distribution using software Fiji/ImageJ under different conditions, which is expected to reveal defects in centromere function and will translate to deficiencies in kinetochore efficiency in coupling the centromeric DNA to the plus ends of spindle microtubules. Our findings have advanced our understanding in this complex physiological process to a great extent and may lead to further optimization of anticancer therapeutics in a mitotic-orientated perspective.
The Role of Kinetochore-Microtubule Functions in Cancer-Initiating Chromosomal Missegregation
Over the past few decades, one of the largest improvements in cancer therapeutic agents has been the use of mitotic poisons. However, as substantially effective as they are, mitotic poisons’ non-selective involvement in other pivotal physiologic processes entail the necessity of carrying out perturbations to novel components that are explicit to the cell cycle/division pathway. Chromosomal abnormalities, known as aneuploidy, is due to a deterioration of mitotic fidelity resulting in chromosomal instability (CIN): a hallmark of cancer. The primary defect behind these abnormalities are improper kinetochore-microtubule (kMT) attachments and the dysfunction of the proteins involved in this process. Therefore, the underlying biological and mechanistic nuances of kMT attachments in mitosis serve as an appealing therapeutic target in light of their central role in accurate, proportionate chromosome segregation. We find that kinetochore/centromere structure and distribution is impeded when the nuclear envelope function is compromised. We computed the centromere intensity and distribution using software Fiji/ImageJ under different conditions, which is expected to reveal defects in centromere function and will translate to deficiencies in kinetochore efficiency in coupling the centromeric DNA to the plus ends of spindle microtubules. Our findings have advanced our understanding in this complex physiological process to a great extent and may lead to further optimization of anticancer therapeutics in a mitotic-orientated perspective.