BioWorld International Correspondent
LONDON - Dividing cells appear to play a tug-of-war game over the pool of chromosomes they need to share, new research suggests. The discovery could help scientists understand what goes wrong when that cellular battle fails to be settled satisfactorily, resulting in cells that have too many chromosomes, or too few.
Tomoyuki Tanaka, principal investigator in the Division of Gene Regulation and Expression at the Wellcome Trust Biocentre at the University of Dundee, UK, told BioWorld International: "Proper inheritance of chromosomes is very important, because if cells do not inherit the right chromosomes, they might die, become transformed into malignant cells or cause congenital diseases such as Down syndrome. Our work is significant because uncovering the mechanism for proper inheritance of chromosomes might provide the chance to discover how diseases such as cancer develop."
Exactly how daughter cells get all their chromosomes has been a mystery until now. All human cells, except eggs and sperm, contain 46 chromosomes. When a cell divides, it first has to copy those chromosomes, which then need to be separated so that a complete set goes to each daughter cell. The pairs of chromosomes remain stuck to each other right up to the moment before cell division takes place.
Researchers had hypothesized that perhaps the existence of some kind of tension between the two sides allowed the daughter cells to ensure that they had connected to the right chromosomes. The work by Tanaka and colleagues, together with a collaborator in Vienna, Austria, now has demonstrated that tension, in the form of a tug-of-war game, plays a key role in achieving correct allocation of the chromosomes.
They report their findings in a paper in the Feb. 11, 2004, issue of Nature, titled "Tension between two kinetochores suffices for their bi-orientation on the mitotic spindle."
Tanaka's group worked on yeast cells, but believes that the mechanism for cell division is the same in human cells. Each chromosome has a centromere (or kinetochore), which functions as a hook onto which the microtubules of the cell attach. Microtubules are rope-like organelles involved in moving cellular components.
Researchers believe that the daughter cells somehow "throw" the microtubules toward the centromeres of the chromosomes, and that one of each pair of chromosomes must be "caught" by each daughter cell.
"The question is, how is this possible?" Tanaka said. "People thought that this might be because the centromeres point in opposite directions, one to each side that would become a daughter cell. As a cowboy catches a wild horse by his lasso, each daughter cell captures chromosomes with the microtubule and drags them to her side before she finally divides from her sister."
The team's data suggest, he said, that cells are able to know if they have captured the right chromosomes or not by playing tug of war for them.
"This game is possible because duplicated chromosomes are still attached to each other when they are captured by the ropes,'" he said. "If cells do not feel a tug, they realize that they have grabbed the wrong chromosomes. In this case, daughter cells have to throw another rope toward a chromosome and repeat this process until they capture the right one."
Tanaka and his colleagues showed that tension, rather than only the orientation of the centromeres, was responsible for allowing the cells to share the chromosomes correctly. The researchers did that by making chromosomes that did not have two centromeres orientated back-to-back as normal, but had them connected by chromatin. Each daughter cell of yeast was still able to successfully capture each centromere on the engineered chromosome by microtubules.
Another aspect of the study examined how the process was regulated. Tanaka's team found that an enzyme called Aurora kinase plays a crucial role in allowing the daughter cells to have a second go at throwing the microtubule toward the chromosome, if they at first attach to the wrong chromosome.
"Without this kinase activity," said Tanaka, "cells cannot make this second attempt. This is very interesting because work by other teams has shown that when Aurora kinase activity goes wrong, sometimes cells become transformed into cancer cells."
The group now is investigating in more detail how Aurora kinase brings about its action.