Faulty DNA-copying may lead to cancer

Scientists have found that 'fragile sites' that can be a breeding ground for human cancers appear in specific areas of the genome where the DNA-copying machinery is slowed or stalled.
Each time a human cell divides, it must first make a copy of its 46 chromosomes to serve as an instruction manual for the new cell. Normally, this process goes off without a hitch.
But from time to time, the information isn't copied and collated properly, leaving gaps or breaks that the cell has to carefully combine back together.
Researchers have long recognised that some regions of the chromosome, called 'fragile sites', are more prone to breakage and can be a breeding ground for human cancers. But they have struggled to understand why these weak spots in the genetic code occur in the first place.

A comprehensive mapping of the fragile sites in yeast by a team of researchers from Duke University showed that fragile sites appear in specific areas of the genome where the DNA-copying machinery is slowed or stalled, either by certain sequences of DNA or by structural elements.
The study, which appears in Proceedings of the National Academy of Sciences, could give insight into the origins of many of the genetic abnormalities seen in solid tumours.

"Other studies have been limited to looking at fragile sites on specific genes or chromosomes," said Thomas D Petes, the Minnie Geller professor of molecular genetics and microbiology at Duke University School of Medicine.

"Ours is the first to examine thousands of these sites across the entire genome and ask what they might have in common," Petes said.
The term 'fragile sites' was first coined in the 1980s to describe the chromosome breaks that appeared whenever a molecule called DNA polymerase - responsible for copying DNA - was blocked in mammalian cells.
Since that discovery, research in the yeast Saccharomyces cerevisiae has shown that certain DNA sequences can make the polymerase slow down or pause as it makes copies. However, none of them have shown how those delays result in fragile sites.
In this study, Petes wanted to find the link between the copier malfunction and its genetic consequences on a genome-wide scale.

First, he knocked down the levels of DNA polymerase in yeast cells to ten-fold lower than normal. Then he used microarray or "gene chip" technology to map where segments of DNA had been rearranged, indicating that a fragile site had once been there.
Researchers found that the fragile sites were associated with sequences or structures that stalled DNA replication, esoteric entities such as inverted repeats, replication termination signals, and transfer RNA genes.
In addition, Petes found that these fragile sites created a surprisingly unstable genome, resulting in a chaotic milieu of rearrangements, duplications and deletions of pieces of DNA or even the gain or loss of entire chromosomes.