How Defective DNA Repair Triggers Two Neurological Diseases

Both disorders arise from defects in a central component of the cell's machinery that repairs damaged DNA, but each disease presents with distinct pathologies. Defects in DNA repair dramatically increase the risk of cancer, which is found in NBS. However, NBS is also characterized by the occurrence of small brain size, or microcephaly, while in contrast, ATLD causes predominantly neurodegeneration.

The research involved the use of mouse models of each the diseases to analyze how the gene defects in ATLD and NBS give rise to the different pathologies. The researchers published their findings in the Jan.15, 2009, issue of the journal Genes & Development.

"Besides shedding light on the rare diseases, the findings may also help to understand how defective DNA repair can selectively affect different organs and how this leads to cancer in some situations," said Peter McKinnon, Ph.D., associate member of the St. Jude Department of Genetics and Tumor Cell Biology and the paper's senior author.

To explore the differences between ATLD and NBS, the researchers used mice engineered to have defects in the causative genes, which produce two proteins that help form a critical component of the DNA repair machinery, called the MRN complex. The MRN complex zeroes in on broken DNA segments and attaches to them. It then recruits another important DNA repair protein, called ATM, to launch the repair process. 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 prevent changes to DNA that lead to cancer.

"Understanding more about how these proteins signal and interact, and how different cells in the body transduce the DNA damage signal, is of fundamental biological importance," McKinnon said. "This knowledge is necessary not only for understanding DNA repair diseases but for understanding the broader implications of maintaining of the stability of DNA."

Other authors of this paper include Erin Shull, Youngsoo Lee, Jingfeng Zhao and Helen Russell (St. Jude); John Petrini and Travis Stracker (Memorial Sloan Kettering Cancer Center and Cornell University Graduate School of Medical Sciences); and Hironobu Nakane (formerly of St. Jude).

This research was supported in part by the National Institutes of Health, the National Cancer Institute and ALSAC.