Mutually Exclusive CBC-Containing Complexes Contribute to RNA Fate

The nuclear cap-binding complex (CBC) stimulates processing reactions of capped RNAs, including their splicing, 3′-end formation, degradation, and transport. CBC effects are particular for individual RNA families, but how such selectivity is achieved remains elusive. Here, we analyze three main CBC partners known to impact different RNA species. ARS2 stimulates 3′-end formation/transcription termination of several transcript types, ZC3H18 stimulates degradation of a diverse set of RNAs, and PHAX functions in pre-small nuclear RNA/small nucleolar RNA (pre-snRNA/snoRNA) transport. Surprisingly, these proteins all bind capped RNAs without strong preferences for given transcripts, and their steady-state binding correlates poorly with their function. Despite this, PHAX and ZC3H18 compete for CBC binding and we demonstrate that this competitive binding is functionally relevant. We further show that CBC-containing complexes are short lived in vivo, and we therefore suggest that RNA fate involves the transient formation of mutually exclusive CBC complexes, which may only be consequential at particular checkpoints during RNA biogenesis. [Display omitted] •PHAX and ZC3H18 compete for binding to the nuclear CBC•PHAX and ZC3H18 have opposite effects on the fate of snRNA precursors and other RNAs•PHAX, ARS2, and ZC3H18 bind capped RNAs without strong preference for given transcripts•CBC-containing complexes are short lived in vivo, with a lifetime of a few seconds The nuclear CBC plays diverse roles in RNA biogenesis and it is not clear how selective effects are achieved for individual RNA families. Giacometti et al. suggest that RNA fate involves the formation of short-lived, mutually exclusive CBC complexes, which may only be consequential at particular checkpoints during RNA biogenesis.