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Research Synopsis for Poets

DNA is hot these days, so you've probably heard a lot about it...DNA fingerprinting, genetic blueprint, yadda, yadda, yadda. With all this positive press, you might not know that DNA is also subject to constant insults (physical, not psychological). Bases (the letters, which make up the rungs of the ladder) can get damaged or even just fall off if the chemical bond holding them on breaks. Or the backbone of the ladder may break, either on just one side or on both. Some of these insults result from exposure to external sources, so you can do things to protect your DNA:

Unfortunately, some DNA damage is caused by internal sources that you can't really prevent. For example, the chemical nature of DNA is such that bases sometimes just fall off. This is thought to occur about 10,000 times every day in every cell in your body. Another example is that when we use oxygen to turn food into energy we produce nasty byproducts, such as free radicals, that can attack and damage our DNA.

Fortunately, our cells have evolved efficient methods for repairing many types of DNA damage. To appreciate how important these repair pathways are, consider life without them. There is a rare hereditary disease called xeroderma pigmentosum (XP) that results from inherited mutations in any of several genes required to repair damage caused by exposure to UV light. Children with XP are extremely sensitive to sunlight, so that even very short exposures cause severe sunburn. Unless appropriate protective measures are taken, children with XP have a 50% chance of developing skin cancer by the time they are 8 years old. Protective measures include never going outside during the daytime (click here to read about a nighttime summer camp for kids with XP), applying sunscreen several times per day, wearing sunglasses and protective clothing, and avoiding other carcinogens that cause damage repaired by NER, such as cigarette smoke and auto exhaust.

Work in our laboratory is aimed at understanding certain types of DNA repair pathways. We are especially interested in the repair that involves recombination. DNA is a double helix, with two strands wrapped around one another. When damage is limited to one strand, as in the case of UV-induced damage, repair is relatively straightforward: the other strand still has all the information intact, so it can act as a template to reproduce the damaged region. When both strands are damaged, however, repair is more difficult. X-rays can cause both strands of the double helix to break. Several chemotherapy agents work by linking the two strands together so they can't be pulled apart; this is toxic to cells that rapidly dividing, which includes (but unfortunately is not limited to) cancerous cells. These two types of damage are often repaired by pathways that involve recombination.

Recombination is just the mixing of DNA from different sources. You have two copies of each chromosome, one from each parent. If one copy of chromosome 21 were to break, the cell can use the other copy of that chromosome to repair it. This is one type of recombination. In general, this repair is a good thing. However, during recombination there is the chance for some information on the broken copy to be replaced with different information from the other copy. We all carry multiple detrimental mutations, but usually on only one of a pair of chromosomes; the other copy provides the normal function. After recombination, it is possible that both copies can carry the same detrimental copy of a gene. This is a major source of tumors in some familial cancer syndromes.

Although this discussion has focused on DNA repair, there are other times when recombination is important. One of these is during meiosis. As we just said, you got one set of chromosomes from each of your parents (that would be your father and your mother). You can only give one of each chromosome to your offspring, so when your body makes sperm or eggs the cells need to separate out the chromosomes and give one of each pair to each egg or sperm. That process depends on recombination because it provides a way to hold each pair together as unit until the sperm or egg progenitor cell is ready to divide and send one set to each daughter cell. Global defects in recombination during meiosis result in sterility, but restricted defects can result in an egg or sperm getting no copies of a particular chromosome or two copies. Having no copies means the embryo will end up with one (from the other parent) instead of two. An embryo lacking a chromosome will spontaneously abort early in development. When the sperm or egg has two copies of a chromosome, the embryo will end up with three copies of that chromosome. This is usually lethal also, but it can result in Down syndrome for chromosome 21. Humans aren't really very good at doing meiosis: It is estimated that 20-30% of all human conceptions fail due to chromosome imbalances. Most of these are never clinically recognized as pregnancy because of spontaneous termination.

Our primary approach to addressing questions about recombination is through genetic manipulation of Drosophila melanogaster, commonly called the fruit fly. Drosophila is one of the premier "model organisms", which researches use to add to our basic understanding of how life works. There are several thousand Drosophila researchers just in the USA. We have also recently begun to use a model organism called Homo sapiens, known commonly as humans. Experimental human genetics takes too long (including getting approval for the experiments), so in ourcase we only work cells in culture.

DNA recombination pathways, like most cellular metabolic pathways, have been largely conserved through half a billion or more years of evolution. We can take a DNA repair gene from the fruit fly and identify the "homologous" gene in humans, mice, nematodes, plants, and even in brewers' yeast (to name a few other famous model organisms). By studying gene function in different organisms, we get a more complete understanding of the pathways through which cells repair DNA and of the functions of specific genes and proteins in these pathways. Our work is not going to lead to immediate treatments for cancer or other diseases. Rather, we add to the understanding of how cells and DNA function, and this in turn leads to a greater understanding of pathogenic situations.

Now that you know all about DNA repair and recombination, please visit other sections of our site. You might be especially interested in the Connections to the Real World page.