UV Damage to DNA Revisited

DNA, or deoxyribonucleic acid, is a remarkable molecule. In addition to encoding the blue prints of an entire organism, it regularly polices itself, detecting errors that occur in its building-block sequence as it replicates. It then remedies the situation by jettisoning the marred region and replacing it with the correct sequence of genetic material.

A contingent of enzymes carries out this vital process of DNA repair. Despite these repair systems, however, errors in DNA sequencesñmutationsñstill occur and are still perpetuated. Cancer is one consequence of mutations caused by faulty DNA repair systems.

Researchers at the University of Rochester in New York have just discovered how a previously unrecognized enzyme enables a cell to ignore its own DNA repair machinery, allowing a mutationña DNA changeñto trigger cancer. Their work focuses on a specific type of damage, that caused by ultraviolet radiation. "UV damage to DNA is the process that leads to skin cancer," says John Nelson, research associate in the department of biophysics at the university.

DNA is a very long molecule that consists of a backbone built of alternating sugars and phosphates, and a sequence of four nucleotide bases, adenine (A), guanine (G), cytosine (C) and thymine (T). The bases form pairs that hold together the two sides of the double helix, A always bonding opposite T, and G opposite C. The task of faithfully replicating a cellís 3 billion base pairs is daunting. It isnít too surprising, then, that sequence changes (mutations) are common.

A mutation may occur spontaneously (when a rare type of a base forms at the precise instant of replication) or from outside agents, such as certain wavelengths of electromagnetic radiation or chemicals. Ultraviolet radiation damages DNA in a very specific way, forming an extra chemical bond between adjacent thymines. The resulting "thymine dimer" forms a small kink in the otherwise sleek double helix. This biochemical bump is enough to disturb replication enzymes so that they insert a mismatched base the next time the cell doubles its DNA in preparation for dividing.

UV-induced thymine dimers are linked to skin cancer because it is the skin that receives the brunt of solar radiation. To cause cancer, the dimers must form in a so-called tumor suppressor gene, usually the p53 gene.

Events of culture or history often reveal environmental aberrations that cause cancer. So it was for the UV-skin cancer connection.

In the 1780s, when Englandís prisons became overcrowded because of laws that incarcerated people on minor charges, the criminal overflow was banished to the east coast of Australia. Large numbers of fair-skinned British were transferred from a cloudy, northern climate to an intensely sunny one. By the 1950s, the association was clear: Fair-skinned descendants of the Australian settlers had the highest skin cancer rate in the world, whereas people of the same ethnic background in England had one of the lowest.

The sun seemed to do its damage earlyñthe higher skin cancer rate applied only to people who had moved to Australia before age 18 or had been born there. The cancer takes many years to develop, which is why those of us who worshiped the sun with aluminum reflectors and baby oil as teens now must be on the lookout for skin cancer lesions. Today in the US, a million new cases of skin cancer are diagnosed each year. Fortunately, the majority of them are the basal or squamous cell types, most of which are easily treated by surgical removal.

The human body responds to UV damage on a cell-by-cell basis. Until the Rochester work, researchers thought that a cell faced only two choices in coping with UV-induced DNA damage: cellular repair or cellular suicide. The suicide process is what biologists call apoptosis and beachgoers call peeling. The Rochester work suggests a third, and frightening, alternative: continuing DNA replication past the irreparable mutation, a response that could knit an error into the DNA sequence and possibly trigger cancer.

In a type of DNA repair called excision repair, thymine dimers are removed and an enzyme called DNA polymerase fills in the correct missing bases, knowing what to do by matching complementary bases (A against T, G against C) on the exposed, other side of the double helix. If for some reason the thymine dimers arenít removed, the polymerase typically comes to a screeching halt, unable to pass the kink. It is a little like a train encountering a boulder on the tracks ahead. Either the kink is removed or the cell doesnít divide.

Discovery of a DNA polymerase that bypasses thymine dimer kinks came from work on yeast, a single-celled organism that nonetheless has complex cells and uses many of the same genes as cells of more complex organisms, including humans. The identification of the new "zeta" polymerase began in 1989 when David Hinkle, associate professor of biology at the University of Rochester, along with biophysics professor Christopher Lawrence, discovered a strain of yeast that is more likely to die from exposure to UV radiation than to develop mutations. That is, when researchers bathed these yeasts in ultraviolet light and allowed them to reproduce, the mutations that would usually occur failed to do so. Either the yeast died or the mutations were fixed, Nelson explains.

The researchers found that these odd yeasts that did not accumulate mutations had a defect in a gene encoding a new enzyme, which the team discovered chemically resembled a DNA polymerase. It was what they now call zeta. If functioning, zeta polymerase enables a cell to replicate its DNA even though UV-induced thymine dimers havenít been completely repaired.

"Replicating past the damaged site is the least-favored mechanism for dealing with DNA damage," says Hinkle, "but from the cellís perspective, itís better to replicate damaged DNA and survive than not replicate and die." Hinkle calls this "a last-gasp system."

Living with mutation may be a viable option for yeast, for which a glitch in a single cell spells death, compared with a peeling skin cell in a many-trillion-celled human. But the consequences of finding zeta polymerase in humans are intriguing. If we indeed have this enzymeñand researchers strongly suspect that we doñit may be responsible for the persistence of certain cancer-causing mutations. And that opens up a new target for cancer prevention.

A drug that blocks zeta polymerase may force a mutated cell to choose between the remaining options: repair or self-destruct.

"If this works the same way in humans," says Hinkle, "then itís conceivable that someday we could inhibit this enzyme in people prone to mutations, such as those receiving chemotherapy or people with a genetic history of cancer."

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