Regulation of superoxide dismutase genes: implications in disease

Abstract

Numerous short-lived and highly reactive oxygen species (ROS) such as superoxide (O2(.-)), hydroxyl radical, and hydrogen peroxide are continuously generated in vivo. Depending upon concentration, location, and intracellular conditions, ROS can cause toxicity or act as signaling molecules. The cellular levels of ROS are controlled by antioxidant enzymes and small-molecule antioxidants. As major antioxidant enzymes, superoxide dismutases (SODs), including copper-zinc superoxide dismutase (Cu/ZnSOD), manganese superoxide dismutase, and extracellular superoxide dismutase, play a crucial role in scavenging O2(.-). This review focuses on the regulation of the sod genes coding for these enzymes, with an emphasis on the human genes. Current knowledge about sod structure and regulation is summarized and depicted as diagrams. Studies to date on genes coding for Cu/ZnSOD (sod1) are mostly focused on alterations in the coding region and their associations with amyotrophic lateral sclerosis. Evaluation of nucleotide sequences reveals that regulatory elements of the sod2 gene reside in both the noncoding and the coding region. Changes associated with sod2 lead to alterations in expression levels as well as protein function. We also discuss the structural basis for the changes in SOD expression associated with pathological conditions and where more work is needed to establish the relationship between SODs and diseases.

Figure 1. Organization of the sod1 gene

The EntrzGeneID of each gene from the NCBI database is indicated on the left. Solid boxes and the associated numbers indicate exons and the size of each exon in base pairs. Lines and numbers between each exon indicate introns and the corresponding size. The regulatory elements in the 5′ flanking region for the human sod1 are expanded and shown in the lower part. The transcription start site is indicated by an arrow and designated +1. Binding sites for transcription factors known to play a regulatory role are placed according to the location of the corresponding regulatory elements identified in published literature and are indicated by numbers on the bottom part of the figure.

Figure 2. Organization of the sod2 gene

The EntrzGeneID of each gene from the database, the size of exons and introns, and the transcriptional start site are organized as described for sod1. The regulatory elements identified in the 5′ flanking region and the second intron of the human sod2 are expanded and shown in the lower part. Corresponding numbers with positive and negative numbers indicate their location relative to the start site, which is designated +1.

Figure 3. Organization of the sod3 gene

The EntrzGeneID of each gene from the database, the size of exons and introns, and the transcriptional start site are organized as described for sod1. The first exon of the human sod3 has been added according to the information extracted from the original publication. This exon was not present in the data base indicated by EntrzGeneID #6649.