RBBP6 anchors pre-mRNA 3′ end processing to nuclear speckles for efficient gene expression

Abstract

Pre-mRNA 3′ processing is an integral step in mRNA biogenesis. However, where this process occurs in the nucleus remains unknown. Here, we demonstrate that nuclear speckles (NSs), membraneless organelles enriched with splicing factors, are major sites for pre-mRNA 3′ processing in human cells. We show that the essential pre-mRNA 3′ processing factor retinoblastoma-binding protein 6 (RBBP6) associates strongly with NSs via its C-terminal intrinsically disordered region (IDR). Importantly, although the conserved N-terminal domain (NTD) of RBBP6 is sufficient for pre-mRNA 3′ processing in vitro, its IDR-mediated association with NSs is required for efficient pre-mRNA 3′ processing in cells. Through proximity labeling analyses, we provide evidence that pre-mRNA 3′ processing for over 50% of genes occurs near NSs. We propose that NSs serve as hubs for RNA polymerase II transcription, pre-mRNA splicing, and 3′ processing, thereby enhancing the efficiency and coordination of different gene expression steps.