Researchers in genome stability have observed that many kinds of cancer are associated with areas where human chromosomes break. Its been hypothesized, but not proven, that slow or altered replication led to the chromosomes breaking.
But now a study at Tufts University two molecular biologists have used yeast artificial chromosomes to prove that hypothesis. They found a highly flexible DNA sequence that increases fragility and stalls replication, which then causes the chromosome to break.
Cancer Causing Areas
The area in question is an area that has a tumor suppressor gene -- a gene whose absence can cause tumors. If you delete that gene or delete part of that gene so it doesn't work anymore, that can lead to tumors. The fact that there is fragility in the same region that this gene is located is a bad coincidence. Fragility can cause deletions and deletions can cause cancer, so you want to understand the fragility because that might be what's causing cancer.
DNA structure leads to fragility
Past research had predicted the flexibility of the DNA helix in this particular common fragile site by calculating the twist angle between consecutive base pairs and found that there were several points of high flexibility, suggesting that the flexibility was connected to the fragility.
Freudenreich and Zhang used yeast artificial chromosomes to test this idea because it allowed them to look at the region in a more detailed way than looking at human chromosomes and to monitor the replication process. They expect the results will be similar when tested in human cells based on previous research using yeast chromosomes.
How the research was conducted
Two regions of predicted high flexibility, plus a region near a cancer cell breakpoint and a control region were tested to see whether any of these regions could cause breakage of a yeast chromosome. They found that one did. This is the first known sequence element within a human common fragile site shown to increase chromosome breakage. What is intriguing is that the sequence that breaks, in addition to being flexible, is predicted to form an abnormal DNA structure." The result is that when replication stalls, chromosomes can break.
How did the chromosomes break?
From past studies, they hypothesized that breakage was connected to replication. Replication is just the duplication of DNA in side the cells as they divide, the DNA inside those cells must duplicate. The research showed that the chromosomes were breaking because replication was stalled.
The problem arises when they do not heal correctly and instead are deleted or rearranged, Cancer cells almost always have some sort of deletions or rearrangements. Something is wrong with their chromosomes that then messes up the genes that are in those areas.
Replication process stalled
The researchers also noticed that this particular sequence was an AT-rich region, where the DNA was composed mostly of the bases adenine (A) and thymine (T), rather than the other bases cytosine (C) or guanine (G). Freudenreich and Zhang found the longer the AT-repeat, the more the replication process was stalled, something they would like to follow up on with further research.
Some researchers believe that the longer the repeat, the more the abnormal the DNA structure forms, and the more fragile the chromosome becomes. What is still up in the air is whether people with longer repeats are more prone to deleting that tumor suppressor gene and getting cancer as a result. Does this correlation between chromosome breaks and cancer has a medical consequence.