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Study Shows How Defective DNA Repair Triggers Two Neurological Diseases
Date:1/14/2009

cess. However, if the damage is too severe, ATM may also trigger programmed cell death called apoptosis. "It happens that defects in ATM also lead to a disease similar to ATLD, highlighting the connections between diseases resulting from defects in this DNA repair pathway," McKinnon said.

The mice engineered to mimic ATLD, like their human counterparts, had defective genes that produce a protein called Mre11; while NBS mice were engineered to have defects in the gene for the protein called Nbs1.

In their experiments, the researchers produced increased DNA-damage stress in the two types of engineered mice, either by using radiation or knocking out a key enzyme that stitches together broken DNA ends.

The researchers then compared the resulting pathologies in the two types of mice. The scientists found that the brain cells of the ATLD mice but not the NBS mice showed a resistance to apoptosis, meaning that the DNA-damaged cells were more likely to survive, even when crippled. Such cells would ultimately die, however, producing the neurodegeneration characteristic of ATLD in humans. In contrast, the NBS mice showed normal apoptosis, but because fewer brain cells survived, developed significantly smaller brains, like their human counterparts.

"Thus, these findings have allowed us to understand how these different mutations in this one DNA repair complex can lead to different neuropathological outcomes," McKinnon said. The findings could also lead to understanding how carriers of the disease genes are more prone to cancer.

"There is a suspicion that people who carry these mutations may be predisposed to cancer and also more susceptible to chemotherapy agents or even to standard X-rays," McKinnon said. "Those agents induce the type of DNA damage that requires the MRN complex and ATM for repair. More generally, studies of the MRN complex and ATM are fundamental to understanding how to preve
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SOURCE St. Jude Children's Research Hospital
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