Completed Genetics & Molecular Biology Cells, Biochemistry & Physiology

Towards a quantitative comprehension of the Spindle Assembly Checkpoint

Funder Wellcome Charity-funded
Recipient organisation Institute of Cancer Research
Funding £2.2M
Period Aug 2018 — Aug 2023

In plain English

AI plain-English summary

Every time a human cell divides, a molecular surveillance system called the spindle assembly checkpoint (SAC) must decide whether to let the cell split its chromosomes or hold it back. This project will count exactly how many molecules of the SAC’s key components are present in a living cell, and measure how fast they move and interact to stop chromosome separation until every chromosome is properly attached. The problem is that we know the SAC’s components in name, but not in number or behaviour. Without this quantitative data, models of how the checkpoint works remain speculative. If the SAC fails, cells can end up with the wrong number of chromosomes—a hallmark of many cancers and developmental disorders. This is fundamental science. It will not produce a drug or a diagnostic test tomorrow. But understanding the SAC’s signalling network with this level of precision could eventually help researchers predict why some cells slip past the checkpoint, and where to look for vulnerabilities in cancer cells that rely on a faulty SAC to survive. Past work on similar molecular counting in other pathways has reshaped how we think about drug targets and cellular decision-making.

View original technical description
My aim is to complete a quantitative analysis of the dynamic signalling pathways that control mitosis. By combining mass spectrometry with cutting-edge microsopy I intend to measure the number of active molecules of the key mitotic regulators and determine how and where they interact to generate a highly responsive signal transduction network that ensures genomic stability by controlling sister chromatid separation and mitotic exit. I have four main aims: 1) Measure the numbers of the mitotic regulators controlling chromosome separation and analyse how they are modulated by post-translational modifications (PTMs). 2) Determine the dynamics of the spindle assembly checkpoint (SAC) in living cells by measuring the generation of the SAC effector complex and the flux of its components through the pathway. 3) Determine how changes to a kinetochore affect its ability to catalyse the generation of the MCC. 4) Determine how a defined change in the number of molecules of specific regulators alters the dynamics and strength of the SAC, and in consequence their effect on genomic stability. Together, these studies will be used to inform and discriminate between models of mitotic control to determine how the SAC combines the properties of potency and responsiveness.

View the original record at the funder ↗

Researchers

Jonathon Pines (EPMC Awardee)

Related Research

Grants with similar aims, by meaning.

The role of the Spindle Assembly Checkpoint in Genomic Stability
Exploring the molecular mechanisms of mitotic spindle formation and organisation: nucleation and anchoring at the centrosome and dynamics at the spindle-kinetochore interface
Dissection of the Function of Microtubule Depolymerases in Mitotic Kinetochore Dynamics
Exploiting chemical genetics to investigate the control of microtubule dynamics by mitotic kinases
Mechanisms of spindle checkpoint silencing

Original classification

Investigator Award in Science

Plain English summaries and category classifications on this site are generated by AI and may not perfectly reflect the original research.