How Defective DNA Repair Triggers Two Neurological Diseases

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2009-01-15 11:04

Scientists at St. Jude Children's Research Hospital have teased apart the biological details distinguishing two related neurological diseases -- ataxia telangiectasia-like disease (ATLD) and Nijmegen breakage syndrome (NBS).

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.

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