For most organisms, mutations—inheritable changes in DNA—provide raw material for evolution. Yet mutations also result in damage, a prospect so potentially serious that organisms have developed more than one mechanism to seek out and repair it. The efficiency of a given repair mechanism depends largely on whether the DNA being repaired is actively being used by a cell. “Evolution can occur because repair is not perfect,” says Michael Smerdon, professor of biochemistry/biophysics.

DNA is an organism’s blueprint for life, and a complete copy of the blueprint is contained within each of an organism’s cells. It’s duplicated whenever a cell divides or grows. It’s transcribed into messenger RNA, then translated into protein, whenever its information is used by a cell.

Because a given cell uses only about 5 percent of its DNA, the effects of DNA damage vary. Sometimes there is no effect, sometimes the cell malfunctions or becomes malignant, and sometimes the cell dies. Because different portions of a cell’s DNA are used at different times in the cell’s life, the effects may be visible either immediately or sometime in the future.

Smerdon’s research focuses on mechanisms that repair DNA actively being used by a cell, DNA that encodes functioning genes and is being transcribed and translated into proteins. Although damage to this DNA can be caused by chemicals and the by-products of normal cellular activities, Smerdon is particularly interested in damage caused by high energy light in the ultraviolet B and C ranges.

Fortunately, the most damaging ultraviolet radiation, UV-C, is absorbed long before it reaches the Earth’s surface by the elements in air. “If it weren’t, biology as we know it would not exist,” says Smerdon. “We would all be dead.” Most UV-B is absorbed by ozone in the stratosphere. Unfortunately, this ozone is destroyed by chlorofluorocarbons, and seasonally high concentrations of these compounds and ozone result in “ozone holes.” Though the hole over Antarctica is the most notorious example, there is also evidence for significant ozone depletion in the northern hemisphere as far south as Scandinavia and North America.

Trained as a physicist, Smerdon moved into biology because of an interest in the structure of DNA. In a cell the double helix strands of DNA are complexed with proteins and packaged into chromatin. Under a microscope, chromatin looks like beads on a string. The beads are DNA tightly wound around proteins, and the string is pure DNA.

“The main function of chromatin is to get all of the DNA into the cell,” says Smerdon. This is no small task, for the DNA that must be stored in each 0.00001-meter-diameter human cell would, if extended to its full length, measure about two meters. And cells hold much more than their DNA.

For the past two decades Smerdon has focused on how chromatin structure modulates both damage to DNA and the mechanisms that repair it.

The most common damage caused by UV-B is the creation of a photodimer, an alteration in the manner which adjacent building blocks of DNA are bound to each other. Each dimer inhibits the ability of the cell to correctly duplicate or transcribe the DNA in that location.

The number of dimers that need repair can be enormous. At the latitude of Pullman, about 40 degrees north, one hour of early summer sunshine results in the introduction of somewhere between 100,000 and 1,000,000 photodimers into exposed skin cells, says Smerdon.

Smerdon’s laboratory was the first to discover that in yeast, some of these repair mechanisms are actually coupled to the process of transcription. Other labs concurrently determined that the same is true for bacteria and rodents. His lab also has determined that UV-B damage to DNA occurs rather evenly throughout the chromatin, whether the DNA is part of the bead or alone in the strand. But damage to the DNA in a bead is modulated by the position of the DNA strand with respect to the proteins. DNA that lies against the proteins is more protected than DNA that faces away from them. DNA repair mechanisms require that the DNA be opened up and made available to the proteins that do the actual repair work. The same is true for DNA that is to be copied or transcribed—the DNA must be available. It is thus not surprising that some of the same proteins are involved in both processes.

Smerdon’s lab has several projects underway designed to elucidate the processes that occur during DNA repair. One collaboration uses tagged DNA building blocks that become incorporated into the DNA as part of the repair process. The tags allow the DNA and associated proteins to be separated from the rest of the DNA and analyzed.

Another project is aimed at understanding why different classes of genes are repaired differently. One of these classes contains the genes used to make the proteins that carry out fundamental cellular processes. Their transcription is controlled by other regions of DNA, called “promoters.” One mechanism for the development of cancer might be for DNA damage to turn on these promoters inappropriately.

However, Smerdon feels that most cancers probably result not from damage in the actively used and repaired areas of a cell’s DNA, but from damage to the quiescent areas. Why? Certainly, repair to these areas is less urgently done. But just as certainly, repair to these areas is necessary for attaining a normal life span in long-lived animals. Most short-lived organisms lack any but the repair mechanisms for active DNA.

There is no doubt that our DNA is constantly being assaulted and damaged and that our repair systems make it possible for us to survive for relatively long periods of time. These systems may not be perfect, but they are extremely efficient.

“Change is necessary for adaptation and for evolution, so the repair systems have to have a little bit of leakage,” says Smerdon. And the imperfections in these systems provide an interesting slant for contemplating our evolutionary journey.

— by Mary Aegerter


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