Cell biologists decipher the signal that ensures that no chromosomes are left behind

Starting as a single cell, organisms go through millions of generations of divisions to ultimately generate the bones, heart, brain and other components that make up a living being. The mainspring in this intricate process is the transfer of DNA through each subsequent cell division into separate packages called chromosomes.

It is essential that all chromosomes are duplicated and accurately distributed in each generation of cell division. If the inherited chromosomal components are altered, even slightly, birth defects and certain types of cancer can occur.

A new study published in the journal Science by postdoctoral fellow Pablo Lara-Gonzalez, Professor in the Division of Biological Sciences Arshad Desai and his colleagues address the mystery of how chromosomes are inherited correctly each time a cell divides. Using a new probe that monitors a key aspect of this process, Lara-Gonzalez and Desai detailed the mechanics behind a “wait” signal that ensures that cell division does not start prematurely.

The researchers focused their investigations on a path in the cell called a “spindle checkpoint”, which is a type of quality control mechanism that ensures accurate chromosomal inheritance during cell division. The spindle checkpoint pathway is activated at a location on the chromosome called kinetochore, a mechanical interface where protein fibers are coupled to separate chromosomes.

“When kinetophores are not attached to these protein fibers, they send a ‘wait’ signal that disrupts the cell in mitosis (cell division), giving time for attachments to form,” said Desai, a professor in the Cell Section. and Developmental Biology (Biological Sciences) and the Department of Cellular and Molecular Medicine (Faculty of Medicine). “In this way, the cell ensures that all chromosomes are connected correctly and ready to be separated before the cell divides, leaving no chromosomes behind.”

At the Science On paper, the researchers describe how the wait checkpoint signal is generated specifically in unbound chromosome kinetocores. Incidentally, they developed a fluorescent probe that allowed them to observe for the first time the key molecular event in the generation of the waiting signal in kinetochores in living cells.

“This work has identified a key ‘matchmaking’ molecule that brings together two constituents of the waiting signal that don’t like to associate on their own,” said Lara-Gonzalez. “These findings help to explain why the ‘wait’ checkpoint signal is generated selectively in the kinetocores and not anywhere else in the cell.”

The findings provide a framework for how the accuracy of chromosome inheritance can be reduced in certain disease states, such as cancer, the researchers said.