Some repair crews just do their job. Others go beyond the call of duty, leaving you better off than you were before the problem occurred. An emergency repair "service" that fixes DNA, the genetic material of cells, belongs to the second type.
Researchers at the Weizmann Institute of Science have now revealed the "trade secrets" of this molecular repair crew, demonstrating how a little genetic material patched into just the right place can save the DNA from a genetic disaster. And while averting a serious mutation, the repair squad leaves behind a surprising calling card: a "good" mutation, which can improve an organism's chance of survival.
DNA is regularly damaged by various factors in the environment, such as ultraviolet radiation. This damage is normally corrected with the help of special proteins known as repair enzymes. Sometimes, however, these enzymes fail to do their job.
Time to call the emergency repairmen. For more than 20 years, scientists have known that apart from the regular repair enzymes, DNA has a last-minute correction mechanism known as the SOS repair. In a study reported on August 28 in Molecular Cell (vol. 2, pp. 191-199),Prof. Zvi Livneh of the Weizmann Institute's Biological Chemistry Department, with graduate students Nina Reuven and Guy Tomer, reconstructed this mechanism in a test tube and revealed how the SOS squad does its job.
The scientists found that when damaged genetic material is not repaired, the defective section of the DNA - usually consisting of one or two "letters" of the genetic code - is simply deleted during replication, and the rest of the DNA molecule shifts to fill in the gap. The result is a disastrous mutation that scrambles the genetic script. This, in turn, leads to the production of defective proteins that can wreak havoc on cellular function. For example, such proteins can turn off the genes that suppress cancer, leading to the development of a tumor, or they can "kill" an essential protein, leading to cell death.
But when the SOS repair does kick in, it replaces damaged DNA with random genetic material. This material acts as a "spacer," keeping the DNA molecule in proper alignment. Similar to the way in which archaeologists fashion clay to fill the gaps between shards of an ancient pot, this "spacer" prevents the damaged genetic letters from being deleted and keeps the overall DNA structure intact.
The SOS repair does not just prevent a genetic catastrophe, it actually provides an "extra" benefit. By introducing random genetic material into the spaces previously inhabited by defective DNA, the SOS mechanism is creating a slightly mutated gene that is still functional and may work even better than the gene in its original form. In fact, such "mild" and beneficial mutations are the driving force behind evolution because they produce genetic diversity that serves as the basis of natural selection.
Understanding of this and other DNA repair mechanisms provides scientists with new insights into diseases such as cancer. Another potential application is in the area of treating bacterial infections. Because the SOS stress response is one of the strategies used by bacteria to resist medications, understanding of this mechanism throws light on the alarming phenomenon of bacterial resistance to antibiotics.
Prof. Livneh holds the Maxwell Ellis Professorial Chair in Biomedical Research. This study was supported by the U.S.-Israel Binational Science Foundation, the Israel Ministry of Science and the Weizmann Institute's Leo and Julia Forchheimer Center for Molecular Genetics.
The Weizmann Institute of Science is a major center of scientific research and graduate study located in Rehovot, Israel.