The discovery could lead to new ways to combat cancer and diseases associated with aging, which are often the result of broken DNA.
The surprising explanation is that the vast majority of DNA breaks stem from a common physical property of DNA itself.
"No chemical insults needed. It is simply a consequence of the DNA molecule," said biophysicist H. Kim, leader of the study published March 12 in the journal eLife.
In 1972, a theoretical physicist named David Bauer predicted that when a single-stranded bubble of DNA forms in the double-stranded helix, it can deform the structure, causing it to buckle. This bubble forms when the DNA molecule, which resembles a twisted ladder, has only the rungs, the flat molecules of DNA known as bases, and is missing the side rails.
Kim's team verified Bauer's prediction, providing the first experimental evidence that DNA bubbles can buckle. These single-stranded bubbles can occur naturally through thermal fluctuations that disrupt the double-helix structure. The team found that as bubble size increases, so does the likelihood that the DNA buckles, leading to a chromosome break.
"A bubble spontaneously forms, and if the bubble is large enough, it buckles," Kim said. "There is no way for a living organism to prevent these natural bubbles."
Because a single-stranded bubble can occur anywhere in the DNA sequence, Kim and his team showed that the breaks associated with the bubble-buckling mechanism can potentially happen at any location in a chromosome. This mechanism of chromosome instability also could provide an explanation for why chromosome rearrangements are common in certain areas of the chromosomes. This phenomenon is seen in cancer genomes and in genomes associated with diseases such as autism.
"This work represents a paradigm shift in the way we think about chromosome instability and potentially many diseases associated with it," said Kim, who is a member of UC Berkeley's Department of Molecular Biology and the Helen Wills Neuroscience Institute.
