Stressed Cells Spark Dna Repair Missteps
When Dr. Susan Rosenberg, professor of molecular and human genetics at Baylor College of Medicine, first published her finding that the mutation rate increased in bacteria stressed by starvation, sometimes resulting in a rare change that benefited the bacteria, it was controversial.
In a report in a recent issue of the journal Molecular Cell, she and her colleagues describe not only how it happens but also show that this only occurs at a special time and place in the stressed cells.
It all begins with the way that the cell repairs breaks in the double strands of DNA that are its genetic blue print. Commonly, when this happens, special protein machinery in the cell copies the missing DNA from another chromosome and rejoins the broken ends around the newly synthesized genetic material.
"It fixes the hole in the DNA by copying similar information," said Rosenberg. However, when the process goes wrong, the repair process introduces errors into the DNA.
When graduate student Rebecca G. Ponder set up a system so that she could control where the break in DNA occurred, she found that errors occurred right next to the break in the stressed cells, and that the rate of errors was 6,000 fold higher than in cells whose DNA was not broken.
"It's really about local repair," said Rosenberg. Not only that, but subsequent experiments proved that this mechanism of increased mutation at sites of DNA repair occurs only in the cells under stress.
"Even if you get a break in a cell, it won't process it in a mutagenic way," said Rosenberg. "The cell repairs it, but does not make mutations unless the cell is stressed.".
The findings support the notion that the increased mutation rate may give the cells a selective advantage, she said. Faced with starvation, most cells do not increase their mutation rate. Then if food becomes available again, they do well.
Among the small percentage that does increase mutations, most of the errors are neutral, not affecting cells at all. A number of are deleterious, resulting in cell death. But a small percentage is advantageous, allowing the cells to survive in an adverse environment.
The fact that the changes in the rate of mutation occur only in a certain physical space at a certain time gives the cells advantage because it reduces the risk to the whole colony. DNA breaks occur only rarely in each individual cell. If the mutations are restricted in time and space, it reduces the risk that the mistakes in repair will affect some other gene. It can also enhance the likelihood of two mutations occurring in the same gene or neighboring genes.
"This can speed evolution of complex protein machines." Rosenberg said.
Natalie C. Fonville also contributed to this research, which was supported by grants from the U.S. Department of Defense Breast Cancer Research Program and the National Institutes of Health.