Every second, countless cells in the human body divide and create new cells. This is one of the most important processes in biology, relying on thousands of molecules working together with incredible precision. However, sometimes the process breaks down in unexpected ways.
Before a cell can divide into two separate cells, it must first copy all of its DNA so that each new cell receives a complete genetic blueprint. In some cases, the DNA may be successfully copied but the cell may not fully divide. The result is a single cell containing twice the normal amount of DNA, a condition known as whole genome duplication (WGD).
To put it simply, it’s like making two copies of a document and accidentally putting both copies in the same folder instead of keeping them separate.
Scientists have long known that duplication of entire genomes can have serious consequences. Cells with extra DNA can no longer function properly, become inactive, die, transform into other cell types, accumulate age-related damage, and cause diseases such as cancer.
Two different ways cells can fail
Researchers at Hokkaido University wanted to understand whether how cells break down during division changes what happens afterwards.
The research team focused on two main causes of whole-genome duplication: cytokinesis failure and mitotic slippage.
When cytokinesis fails, the cell completes almost the entire division process, but fails at the final stage of physically dividing into two separate cells. In mitotic slippage, the cell begins the division process, but the cell divides too quickly before the chromosomes are properly separated.
“Whole-genome duplication occurs through multiple cellular processes, but it was unclear whether differences in the pathways influence the properties of the resulting cells,” says Associate Professor Ryota Uehara, corresponding author of the study.
Both mistakes double the cell’s DNA, but the researchers found that the results were dramatically different.
Why do some DNA-doubled cells survive?
The scientists used live-cell imaging and chromosome-specific labeling techniques to track how cells behave after undergoing whole-genome replication through two different mechanisms.
Cells created by failed cytokinesis are more stable and more likely to survive. However, cells generated by mitotic slippage often exhibit uneven chromosome distribution and have low survival rates.
Researchers have found that chromosome composition is a key factor behind these differences.
In mitotic slippage, chromosomes often divide unevenly, creating severe genetic imbalances and reducing cell viability. In cytokinesis failure, the distribution of chromosomes is more balanced and the cell is more stable.
The researchers also found that experimentally improving chromosome segregation in cells undergoing mitosis significantly increased cell survival.
Impact on cancer research
This discovery could have important implications for cancer treatment and prevention.
Whole-genome duplications are common in cancer cells, and some cancer treatments can also unintentionally cause them. Cells that survive after acquiring extra DNA can continue to proliferate, potentially contributing to tumor recurrence.
New research suggests that targeting the chromosome segregation process may help prevent abnormal cells from continuing to survive and proliferate.
“There are many different mechanisms by which whole-genome duplication occurs, but its clear consequences have been largely ignored,” Uehara says. “We challenged this conventional view by comparing cells formed by different mechanisms and found that these differences can influence cell behavior over time.”
