Noncanonical Functions of DICER-Mediated Pathways

Dicer has long been viewed as the RNAse III enzyme that generates small regulatory RNAs to drive RNA interference (RNAi) machinery and posttranscriptional gene silencing. However, a growing body of evidence reveals that Dicer's functional landscape extends far beyond its canonical role in the cytoplasmic RNAi pathway. In this review, we delineate the classical, RNAse III-dependent small RNA processing activities from an expanding set of noncanonical functions in which Dicer operates independently of RNAi outputs. We highlight emerging principles that underlie these functions, including structural and regulatory principles, with a focus on nuclear functions, posttranslational regulation, and noncanonical substrates. We then explore how Dicer intersects with genome integrity pathways, transcriptional programs, and cellular response to DNA damage. Finally, we propose an integrated conceptual framework in which Dicer acts as a multifunctional regulator of chromatin architecture and genome stability, as we consider how perturbations of these pathways contribute to disease.