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The ease with which this lesion is formed and detected has made 8-oxoguanine the subject of intense research. That, coupled with a number of other factors, has made it one of the best characterized DNA lesions, notes Sheila S. David, an associate chemistry professor at the University of Utah. But recent work suggests that other DNA modifications caused by oxidation may also endanger cells. Cells hold dear the genetic information contained in their DNA and work diligently to maintain its sequence. The threat of DNA damage comes in many flavors. Among the troublemakers are breaks in the DNA helix and modification of DNA bases by anticancer drugs, alkylating agents, or oxidants. One of the best studied of these modifications, oxidative damage, is caused by reactive oxygen species (most often hydroxyl radicals) as well as other chemical agents. Produced by everything from the sun's ultraviolet light to chemicals in our diet to normal metabolic activity, these reactive species modify the nucleotide bases that make up DNA. One of the most common alterations is the addition of a ketone group to a guanine base to form the aforementioned 8-oxoguanine--officially known as 8-oxo-7,8-dihydroguanine. The interest in this alteration was natural. For one, 8-oxoguanine lesions give rise to potentially deleterious DNA mutations. The extra oxygen atom on 8-oxoguanine allows the damaged base to adopt a glycosidic bond conformation that is different from the one favored by guanine bases in the DNA helix. When it assumes this abnormal conformation, 8-oxoguanine pairs up with adenine (normally thymine's partner in the DNA helix) instead of cytosine (guanine's normal partner). So when cells replicate their DNA, some DNA polymerases tend to mistakenly pair 8-oxoguanine with adenine instead of cytosine. If this 8-oxoguanine:adenine mismatch isn't repaired before the cell again replicates its DNA, it will give rise to a thymine:adenine base pair where a guanine:cytosine base pair should be. Such guanine:cytosine to thymine:adenine mutations can be devastating, David points out, because cells rely on the structural integrity of their DNA to transmit genetic information from one generation to the next. In response, cells have developed a comprehensive DNA repair system to find and remove 8-oxoguanine--a fact that she says further illustrates this lesion's importance. THIS SYSTEM begins with prevention: An enzyme called Mth1 cleanses the pool of nucleotide triphosphate DNA-building blocks of 8-oxoguanine lesions. This stymies the incorporation of preformed 8-oxoguanine into DNA during replication. To take care of 8-oxoguanine lesions that have already made their way into the DNA duplex, cells turn to a DNA repair enzyme called oxoguanine glycosylase/lyase (Ogg1). Ogg1 finds and removes any 8-oxoguanines that are opposite cytosine in duplex DNA. Other enzymes fill in the gap, restoring the undamaged guanine:cytosine pair. But on occasion, damaged DNA strands are accidentally replicated before an 8-oxoguanine lesion is removed, creating an 8-oxoguanine:adenine mismatch. In these cases, an enzyme called Myh catalyzes the removal of the unwanted adenine. Other enzymes then replace it with cytosine, yielding an 8-oxoguanine:cytosine base pair that is repaired via the Ogg1 pathway. Together, these factors--the frequency with which this lesion forms, its tendency to cause DNA mutations, and the complex DNA repair machinery cells have evolved to combat it--have made 8-oxoguanine the center of attention. Nor should we overlook the products of further oxidation of 8-oxoguanine, says organic chemist Cynthia J. Burrows, professor of chemistry at the University of Utah. 8-Oxoguanine's very low redox potential makes it highly susceptible to further oxidation. Burrows suspects these further oxidized products will prove even more dangerous than 8-oxoguanine. Burrows has figured out how to synthesize oligonucleotides containing two other products of further oxidation of 8-oxoguanine: spiroiminodihydantoin and guanidinohydantoin. She and David have shown that these lesions are poorly repaired and that polymerases tend to pair them with adenine or guanine--but never guanine's normal partner, cytosine. Burrows and Essigmann are now collaborating to measure how mutagenic these two lesions are to bacteria. Utah's David and medical geneticist Julian R. Sampson of the University of Wales College of Medicine have shown that there's a direct link between inherited defects in Myh--one of the enzymes that helps repair 8-oxoguanine lesions--and patients' propensity for contracting colon cancer [Nat. Genet., 30, 227 (2002). They found that members of a British family affected by multiple colorectal cancers have two different mutations in the gene coding for Myh. These two mutant forms of Myh both remove adenine mispaired with 8-oxoguanine much less efficiently than the wild-type enzyme does. The reduced activity of the mutant Myh enzymes found allows mutations to persist, permitting mutations to accumulate in a particular gene that causes colon cancer in these patients. "This is the first evidence for an association between inherited defects in the repair of oxidative lesions and predisposition for cancer in humans," David tells C&EN. "And it's sure to spark even more interest in the chemistry of these lesions and the biochemistry of their repair," she adds. |
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