ERH promotes primary microRNA processing beyond cluster assistance

MicroRNA (miRNA) maturation is initiated by the Microprocessor complex, comprising DROSHA and DGCR8, that processes primary miRNAs (pri-miRNAs). Recent studies have identified ERH and SAFB2 as auxiliary factors that enhance the functionality of the Microprocessor. These factors are required for cluster assistance, where optimal pri-miRNAs facilitate the processing of adjacent suboptimal pri-miRNAs. However, the specific action mechanisms of ERH and SAFB2 have not yet been defined. In this study, we found that ERH broadly enhances the processing of pri-miRNAs regardless of their genomic contexts, affecting both stand-alone and clustered ones. Suboptimal hairpins are affected more prominently by ERH knockdown than efficiently processed hairpins. In contrast, SAFB2 specifically supports the processing of suboptimal pri-miRNA hairpins within clusters. This study reveals the distinct roles of ERH and SAFB2 in cluster assistance and presents a new model, in which SAFB2 facilitates the Microprocessor's transfer between hairpins, while ERH enables the efficient processing of suboptimal pri-miRNAs. MicroRNA maturation is initiated by the Microprocessor that cleaves primary microRNA hairpins. Here, the authors uncover distinct roles of two auxiliary factors of the Microprocessor, ERH and SAFB2, in the processing of suboptimal clustered microRNA hairpins.