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Discovery links rare, childhood neurodegenerative diseases to common problem in DNA repair
Date:5/9/2014

to understand how this newly recognized source of DNA damage might contribute to tumor development or the age-related DNA damage in the brain that is associated with neurodegenerative disorders like Alzheimer's disease," said co-corresponding author Peter McKinnon, Ph.D., a member of the St. Jude Department of Genetics. The co-corresponding author is Sachin Katyal, Ph.D., of the University of Manitoba Department of Pharmacology and Therapeutics and formerly of St. Jude.

A-T and SCAN1 are caused by mutations in different enzymes involved in DNA repair. Mutations in the ATM protein lead to A-T. Alterations in the Tdp1 protein cause SCAN1.

Working in nerve cells growing in the laboratory and in the nervous system of specially bred mice, researchers showed for the first time that ATM and Tdp1 work cooperatively to repair breaks in DNA. Scientists also demonstrated how the proteins accomplish the task.

The results revealed a new role for ATM in repairing single-strand DNA breaks. Until this study, ATM was linked to double-strand DNA repair. ATM was also known to work exclusively as a protein kinase. Kinases are enzymes that use chemicals called phosphate groups to regulate other proteins.

Scientists reported that when Top1ccs are trapped ATM functions as a protein kinase and alert cells to the DNA damage. But researchers found ATM also serves a more direct role by marking the trapped Top1ccs for degradation by the protein complex cells use to get rid of damaged or unnecessary proteins. ATM accomplishes that task by promoting the addition of certain proteins called ubiquitin and SUMO to the Top1cc surface.

Tdp1 then completes the DNA-repair process by severing the chemical bonds that tether Top1 to DNA.

Mice lacking either Atm or Tdp1 survived with apparently normal neurological function. But compared to normal mice, the animals missing either protein had elevated levels of Top1cc. Those levels rose sharply during pe
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Contact: Carrie Strehlau
carrie.strehlau@stjude.org
901-595-2295
St. Jude Children's Research Hospital
Source:Eurekalert

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