H2O2 Switcheroo
A group of researchers at Rutgers Cancer Institute of New Jersey have discovered a new role for the long-studied enzyme superoxide dismutase (Sod1). The researchers, led by Dr. Steven Zheng, show that Sod1, previously known as a key player in the reduction of superoxide byproducts, also plays a role in controlling the oxidative stress response at the transcriptional level. The findings, published in Nature Communications, could have implications for the diagnosis and treatment of some cancers and neurological diseases.
Sod1 has been known for nearly half a century as an enzyme responsible for reducing superoxide byproducts created during cell metabolism. These superoxides belong to a family of byproducts known as the reactive oxygen species (ROS) that covalently modify and damage lipids, proteins, and DNA and RNA. The damages and genomic instability caused by ROS are major contributing factors in the development of cancer and several neurological diseases as well as age-related complications.
Zheng and colleagues show that in addition to its known role dismutating superoxides, Sod1 also aids in maintaining genomic stability during oxidative stress. The researchers observed that when cells have high levels of hydrogen peroxide – an additional ROS – Sod1 translocates to the nucleus and acts as a transcription factor for numerous oxidative resistance and repair genes.
The researchers report that nuclear localization of Sod1 is activated by its interaction with the kinase Dun1. By binding to and phosphorylating Sod1, Dun1 activates the nuclear transport and transcriptional regulatory function of Sod1.
This Dun1 phosphorylation is mediated by ataxia telangiectasia mutated (ATM), a protein that acts as a tumor suppressor and is also associated with several neurological diseases. ATM senses elevated levels of hydrogen peroxide and mediate the Sod1-Dun1 interaction, thus leading to the nuclear localization of Sod1.
The findings help to explain why ATM and Sod1 share common traits in some cancers and neurological disorders. Sod1 plays a key role in the development of liver and lung cancer and is known to be a major underlying factor for inherited amyotrophic lateral sclerosis (ALS) or Lou Gehrig’s disease. Sod1 is also associated with several age-related disorders including macular degenerations and muscle atrophy.
Lead author Steven Zheng says that by identifying this new role for Sod1 in helping to control oxidative stress response, researchers can better understand the relationship between Sod1 and ATM and their collective impact on ROS byproducts. “Further research in this area could have considerable implications for the diagnosis and treatment of Sod1-related diseases such as ALS and cancer,” says Zheng.
