See Rialdi et al., Science 352 aad7993
Topoisomerase I (Top1) represents an exciting new target in regulating host defense against pathogenic insult. Specifically, the balance between pro- and anti-inflammatory outcomes depends critically on equilibrium levels of endogenous Top1. Pharmacological intervention of Top1 action in chromatin therefore represents a novel and exciting inroad in treating acute inflammation which can be lethal in some cases.
Why is this exciting?
The innate immune response is a pivotal and early onset protection mechanism against microbial and viral pathogens. This response, like many pathways, is wholly dependent upon gene expression of a panoply of genes that encode “pattern recognition receptors” which are directed to pathogen-associated molecular patterns (PAMPs). Thus, PAMP responsive genes largely govern and regulate the innate immune system, and are essential; therefore, inappropriate regulation of these genes is detrimental. There is evidence that over expression of at least some of these genes can be lethal. For example, Rialdi et al note that unregulated up-expression of proinflammatory genes, in response to microbial PAMPs, may lead to tissue or organ defects with severe collateral damage. Their idea to target basic factors that control this response has real merit. Top1 is an excellent choice in this context for several reasons: 1) it regulates DNA topology associated with DNA templating (reading the sequence) and transcription; 2) limiting endogenous levels of Top1 will grind transcription to a halt due to accumulation of superhelical tension; 3) accumulated superhelical tension will mitigate transcription of a wide array of genes; 4) Top1 is ubiquitous in tissues and should be viewed as a basic chromatin remodeling factor that largely impacts genes that require nucleosome revision (these genes are largely responsible for proinflammatory defects). Finally, it is worth noting that Top1 poisons, such as camptothecin/Topotecan, will induce Top1/DNA covalent complexes on many genes, but the activity on inflammatory genes is independent from DNA damage. Regardless, the development of more potent catalytic inhibitors is key for translating this findings to the clinic.
Rialdi et al correctly posit that mitigating Top1 action offers a new inroad to treating diseases that cause death by proinflammatory mechanisms, such as ebola, influenza and Staphylococcus aureus. What is needed now is a highly specific catalytic inhibitor (small molecule, natural product or synthetic) that can diffuse into nuclei to tone down Top1 catalytic action. Such a compound has yet to be identified; nonetheless, a Top1 catalytic inhibitor probably does exist.
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