It takes two to cleave: the logic of cluster assistance

Mature microRNAs are generated in a series of sequential processing steps, creating multiple opportunities for regulatory bottlenecks. In this issue of Genes & Development, Shang and colleagues (doi:10.1101/gad.353316.125) dissect microRNA biogenesis by cluster assistance in human cells, demonstrating that ERH and SAFB2 have distinct functions in the processing of suboptimal hairpins. Beyond resolving the mechanistic dependencies on ERH and SAFB2, the study demonstrates that cluster assistance has been co-opted into a feedback mechanism to regulate DGCR8 levels and Microprocessor stability, elevating cluster assistance from a descriptive phenomenon to a physiologically integrated miRNA regulatory pathway.