A new function of copper zinc superoxide dismutase: as a regulatory DNA-binding protein in gene expression in response to intracellular hydrogen peroxide

Abstract

In microorganisms, a number of metalloproteins including PerR are found to regulate gene expression in response to environmental reactive oxygen species (ROS) changes. However, discovery of similar regulatory mechanisms remains elusive within mammalian cells. As an antioxidant metalloenzyme that maintains intracellular ROS homeostasis, copper zinc superoxide dismutase (SOD1) has high affinity for DNA in solution and in cells. Here, we explored the regulatory roles of SOD1 in the expression of genes in response to ROS changes within mammalian cells. SOD1-occupied DNA sites with distinct sequence preference were identified. Changing ROS levels both were found to impact DNA–SOD1 interactions in solution and within HeLa cells. GGA was one of the base triplets that had direct contact with SOD1. DNA–SOD1 interactions were observed to regulate the ROS-responsive expression of functional genes including oncogenes and amyotrophic lateral sclerosis-linked genes in transcriptional phases. Our results confirm another function of SOD1, acting as a H 2 O 2 -responsive regulatory protein in the expression of numerous mammalian genes.

Premature termination codons in SOD1 causing Amyotrophic Lateral Sclerosis are predicted to escape the nonsense-mediated mRNA decay

“…Recently it has been demonstrated that SOD1 acts as a H 2 O 2 -responsive regulatory protein in the expression of ALS-linked genes. Both sequence preference and affinity of SOD1 interactions with DNA depend on SOD1 conformation 21 . Thereby, PTCs that escape NMD in SOD1 are expected to cause toxic conformational changes.…”

Insights on the Effects of Resveratrol and Some of Its Derivatives in Cancer and Autoimmunity: A Molecule with a Dual Activity

“…Among the oxidative lesions in DNA there are not only strand breaks but also base modifications, sugar damage, and abasic sites [29]. Due to the ability of oxidants, antioxidants and other determinants of the intracellular redox state to modulate gene transcription, ROS changes within mammalian cells can also modify the expression of numerous mammalian genes, such as oncogenes and amyotrophic lateral sclerosis-linked genes during transcription, as recently demonstrated by Li [30].…”

Mechanisms of SOD1 regulation by post-translational modifications

“…Tsang et al [14] found that in response to toxic levels of oxidative stress (0.4 mM H 2 O 2 ), SOD1 translocates to the nucleus to transcriptionally upregulate antioxidant genes. In addition, this new nuclear function of SOD1 was recently shown to involve direct SOD1-DNA interactions with specific DNA sequence preferences [15]. The nuclear translocation of SOD1 is dependent on activation of ATM/Mec1 by ROS, which promotes SOD1 binding to the Chk2-related kinase, Dun1.…”

“…These findings suggest that the large majority of SOD1 (>99%) may be required for functions outside its canonical role in dismutating superoxide. Indeed, SOD1 is reported to function in cellular zinc [12] and copper buffering [13], as a nuclear transcription factor to control the expression of antioxidant genes [14,15] and for peroxide-mediated redox signaling [11].…”