Target-specific requirements for RNA interference can be explained by a single regulatory network.

RNA interference (RNAi) is a widely used mechanism for silencing the expression of genes to combat disease or improve agriculture. We show that different genes can show stark differences in their requirements for particular regulators of RNAi despite silencing relying on a single regulatory network. These differences are explained by genes having different thresholds for silencing such that genes with high thresholds for silencing require multiple regulators of RNA silencing for efficient knockdown. When such genes are targeted, resistance through mutations becomes more likely, necessitating another round of drug development. Anticipating these mechanisms for the development of resistance before widespread use of an RNAi-based drug or treatment will be crucial for avoiding futile cycles of innovation.