New Clues To How Body Repairs DNA Damage Result From Investigation Of Rare Hereditary Disorder |
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| By Jeffery Kahn, jbkahn@lbl.gov April 24, 1997 |
BERKELEY, CA -- Oxidative damage has been implicated in a range of diseases including cancer, atherosclerosis, neurodegenerative diseases such as Parkinson's and Alzheimer's, and even aging. Now, researchers believe they have linked it to Cockayne syndrome, a rare hereditary disorder in which infants suffer severe developmental failure and early death.
In papers published April 1 in the Proceedings of the National Academy of Sciences and February 14 in Science magazine, the research team led by Priscilla Cooper of Ernest Orlando Lawrence Berkeley National Laboratory (Berkeley Lab) provides the first evidence that Cockayne's results from mutations that prevent the body from rapidly repairing oxidative damage to DNA. In pinpointing what goes wrong during Cockayne's -- a disease where normal development is severely impaired -- the findings also shed new light on how vital DNA repair processes must work in order for normal development to occur.
The research team includes Stuart Clarkson and Thierry Nouspikel of the University of Geneva Medical Center in Switzerland and Steven Leadon of the University of North Carolina.
Currently, there is no treatment for Cockayne's. Babies born with this syndrome appear fairly normal at birth but fail to develop normally. During their short lives, they become dwarved and have other skeletal abnormalities. Though they are profoundly retarded, these children typically are very friendly and very interested in people. In most cases, they die in infancy or childhood.
Up until now, the prevailing theory has been that Cockayne's was due to subtle defects in transcription. That is, scientists believed that these children's genetic machinery for synthesizing proteins needed by the body does not operate at normal capacity. Over time, went this theory, this results in developmental failure and death.
Cooper and company have found a different explanation. Their new findings focus on how the body deals with the repair of oxidative damage.
Every minute, the body pumps 10 to 20 liters of oxygen through the blood, carrying it to billions of cells in our bodies. In its normal molecular form, oxygen is harmless. However, cellular metabolism involving oxygen can generate several highly reactive forms of oxygen called free radicals. These free radicals can cause oxidative damage to cellular components including the DNA.
In an average human cell, several thousand lesions occur in the DNA every day. Many of these lesions result from oxidative damage. Each lesion -- a damaged section of DNA -- must be snipped out and the DNA repaired to preserve its normal function. Unrepaired DNA can lose its ability to code for proteins. Mutations also can result. These mutations can activate oncogenes or silence tumor suppressor genes.
Normal cells efficiently recognize and repair damaged sections of their DNA. In fact, Cooper and her colleagues have found that the repair of oxidative damage occurs faster in active genes (which make up less than five percent of the genome) than in inactive regions of the DNA. In the case of children with Cockayne syndrome, Cooper says these latest findings establish that oxidative damage to active genes is not preferentially repaired, and in the most severe cases, repair is slowed throughout the whole genome. The resulting accumulation of oxidative damage could impair the normal functions of the DNA and may even result in triggering a program of cell death (apoptosis).
"We have not yet proved this is the case. However," says Cooper, "we have shown a very strong correlation between the inability to repair oxidative damage and severe developmental failure and early death. We believe that the inability to repair oxidative damage is the underyling cause of Cockayne's."
Cooper, who is a member of Berkeley Lab's Life Sciences Division, says one novel implication of the research is that two repair mechanisms thought to be independent of one another appear to work together to repair oxidative DNA damage.
Nucleotide excision repair (NER) removes many types of DNA damage including lesions produced by chemical carcinogens or sunlight, either of which can cause cancer if not repaired. This repair process is general in nature, snipping out defective stretches of DNA that consist of some 30 nucleotides. The process is initiated not because of the recognition of a specific defect but because of the detection of a general distortion produced in the DNA helix by lesions. Until now, NER was thought to be the only repair process that can select the transcriptionally active portion of the genome for preferential repair.
In contrast, base excision repair (BER) relies on specialized enzymes to recognize and repair very specific types of damage including the damage produced by free radicals. This process cleaves and repairs a section of DNA consisting of one to five nucleotide bases.
After tackling what amounts to a mind-twisting scientific brain teaser, Cooper and colleagues reached the conclusion that NER and BER work together to repair oxidative damage.
Cockayne syndrome can result from defects in any of five separate genes. Different defects in three of these genes can cause another disease called xeroderma pigmentosum (XP), which is not clinically related to Cockayne's. Individuals with XP, which is known to be a repair-deficiency disease, are extremely sensitive to ultraviolet light and chemical carcinogens, and are highly susceptible to skin cancer.
To solve the puzzle, the research team focused on the XPG gene, one of the genes that can result in either of the two diseases. It is among a family of seven genes all of which are necessary for NER and any one of which, when defective, can result in XP. As reported in Science, they showed that oxidative damage is removed normally by BER from the cells of XP patients who have NER defects only, but not from those patients who have Cockayne's due to defects in the XPG gene. Thus, they concluded, one normal function of the XPG gene is to play a role in the removal of oxidative lesions by BER. The researchers report that some mutations in this gene destroy its ability to function in NER, thus causing XP. Different mutations also destroy its ability to direct efficient removal of oxidative damage by BER, and result in Cockayne syndrome.
Currently, Cooper's group is investigating what goes wrong with BER in Cockayne's patients. Eventually, resolution of this biochemical conundrum could have medical and pharmaceutical implications not only for children born with Cockayne syndrome but for those afflicted with other repair-deficiency disorders.
Berkeley Lab conducts unclassified scientific research for the U.S. Department of Energy. It is located in Berkeley, California and is managed by the University of California.
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