How cells fight against chromosome imbalance

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Most living cells have a defined number of chromosomes: for example, human cells have 23 pairs. As cells divide, they produce errors that cause chromosomes to be acquired or lost, which is often very harmful.

For the first time, MIT biologists have discovered a mechanism by which the immune system eliminates these genetically unbalanced cells from the body. After acquiring or losing a chromosome, the cell signals almost immediately, recruiting immune cells called natural killer cells, thereby destroying abnormal cells.

These findings increase the likelihood of using the system to kill cancer cells, which are almost always too many or too few chromosomes.

"If we can reactivate this immune recognition system, it would be a very good way to get rid of cancer cells," said Katikaen and Curtis marble professor Angelika Amon of the Massachusetts Institute of Technology's Cancer Research. Koch Comprehensive Cancer Institute, senior author of the study.

Stefano Santaguida, a research scientist at the Koch Institute, is the lead author of the paper, published in the June 19 issue of Developmental Cell. "spiral down"

Before cell division, its chromosomes replicate and then align in the middle of the cell. When a cell divides into two daughter cells, half of the chromosomes are pulled into each cell. If these chromosomes are not properly separated, this process leads to an imbalance in the number of chromosomes in the daughter cells - a state called aneuploidy.

When aneuploidy occurs in embryonic cells, it is almost always fatal to the organism. For human embryos, extra copies of any chromosome are fatal, except for chromosome 21, which produces Down's syndrome; chromosomes 13 and 18, leading to developmental disorders called Patau and Edwards syndrome; and X and Y sex chromosomes Additional copies may cause various diseases, but are usually not fatal.

In recent years, Amon's lab has been studying the obvious paradox of aneuploidy: when normal adult cells become aneuploid, it impairs their ability to survive and proliferate; however, cancer cells are almost all non-holistic The ploidy can grow uncontrolled.

"Aneuploidy is very harmful in most cells. However, aneuploidy is highly correlated with cancer and is characterized by upregulated growth. Therefore, a very important question is: if aneuploidy impedes cell proliferation Why are most tumors aneuploid?" Santaguida said.

To try to answer this question, the researchers wanted to know more about how aneuploidy affects cells. In the past few years, Santaguida and Amon have been studying what happens immediately after the chromosomes are erroneously separated, resulting in daughter cell imbalance.

In this new study, they studied the effect of this imbalance on the cell division cycle by interfering with the process by which the correct chromosomes were attached to the spindle, which is the structure that keeps the chromosome at the equator of the cell before division. This interference causes some chromosomes to lag and is dragged into two daughter cells.

The researchers found that after the cell first undergoes the first division, some of the chromosomes are unevenly distributed, which quickly triggers another cell division, resulting in more chromosomal imbalances and significant DNA damage. Eventually, the cells completely stopped dividing.

"These cells are in a spiraling state, they start to have a little genomic confusion, and things are getting worse," Amon said.

"This paper is very convincing and clearly shows that when chromosomes are lost or acquired, the initial cells cannot judge whether their chromosomes are mis-segregated," said David Pellman, professor of pediatric oncology at the Dana-Farber Cancer Institute, who did not participate. In the study. "In contrast, chromosomal imbalances lead to cell defects and protein and gene imbalances that can severely disrupt DNA replication and cause further damage to the chromosome."