In an exciting new paper by Ahmad et al (1), a new RNA topoisomerase function as been ascribed to several pro and eukaryotic DNA topoisomerase activities. While others have evidence for such interesting and novel activity on an RNA single stranded substrate, this paper addresses some new questions. Specifically, what is the prevalence of RNA topo enzymes?; where do the key domains required for RNA vs DNA topological interplay?, and; do they all behave like hTop3b and co-habitate polyribosomes? In a surprising outcome, the authors provide new evidence that RNA topo activity is built into Type IA enzymes (like topo I omega protein from E. coli) in all life forms tested. Perhaps even more importantly is this finding: the same catalytic residue is utilized for both RNA and DNA topo activities; however, the less conserved C-terminal domain is not required. Another surprise? While RNA topo from animal species appears to work on polysomes, the cognates from yeast and bacteria do not. A foundational role for RNA topo function in the epigenetic process is highly significant. Specifically, a requirement to resolve topological problems with mRNA reading suggests a fundamental role in gene expression. This study raises more questions about double duty behavior of DNA/RNA topoisomerases. Notably, drug screens for new antibiotics and anticancer agents have singularly focused on the DNA topoisomerase side of the equation. Such screens would naturally miss the RNA targeting potential. A new look into screening RNA topo function may be important in future work. A good, HTS (Hi Throughput) RNA based screen should be developed for this in mind.
Another question is whether existing anti-topo1 drugs might function at the RNA-topo level. This should be re-evaluated and is probably worthy of detailed study. Finally, what happens when you covalently trap an RNA-Topo intermediate? It seems that RNA topoisomerases acting on any unfolded single stranded RNA might be immediately converted to covalent complexes. This in turn raises another question: How important is the duplex region for activity. A hint comes from the fact that the RNA topoisomerase behavior of Type IA enzymes may have been missed due the low level of RNA duplex structuring of the substrate.
While at first this may seem like a daunting task, over time we have been able to break it down to its core components. As it is unpacked we find what this means for health, medicine, and the benefits of this knowledge. There is a great interview published on anipots that speaks of this matter with an expert that further simplifies the topic.
1. Ahmad et al. (2016) RNA topoisomerase is prevalent in all domains of life and associates with polyribosomes in animals. Nucleic Acids Research doi: 10.1093/nar/gkw508 Published on line June 1, 2016