Ribonucleotide reductase (RNR) is the rate-limiting enzyme in the de novo synthesis of deoxyribonucleoside triphosphates and it plays crucial roles in cellular DNA replication and repair. Mammals contain one large subunit RRM1 and two small subunits: RRM2 and the newly identified p53R2. The active RNR is a heterotetramer composed of two large and two small subunits, and both large and small subunits are required for the enzymatic activity. Results from previous studies indicate that abnormal expression of RNR subunits is closely associated with the development and progression of various human diseases including tumors and mitochondrial diseases.  

A research group led by Prof. Zongbin Cui at Institute of Hydrobiology, Chinese Academy of Sciences (IHB), has investigated the control of p53R2 gene expression in zebrafish and the roles of p53R2 in DNA synthesis and repair [2011, Gene, 475(1):30-38]. This group further demonstrated the control of RRM2 gene expression through alternative promoters, splicing and polyadenylation sites in zebrafish.  

Three functional RRM2 promoters were identified to generate six transcript variants with distinct 5′ termini. The proximal promoter contains a conserved E2F binding site and two CCAAT boxes, which are crucial for the transcription of RRM2 gene during cell cycle. Activity of the distal promoter can be induced by DNA damage to generate four transcript variants through alternative splicing.  

In addition, two novel splice variants were found to encode distinct N-truncated RRM2 isoforms containing residues for enzymatic activity but no KEN box essential for its proteolysis. These two N-truncated RRM2 isoforms remained in the cytoplasm and were able to interact with RRM1. These findings suggest that multilayered mechanisms control the differential expression andfunctionof zebrafish RRM2 gene during cell cycle and under genotoxic stress. 

The results were published on August 24, 2011 in PLoS ONE（http://dx.plos.org/10.1371/journal.pone.0024089）.