CBC–ARS2 stimulates 3′-end maturation of multiple RNA families and favors cap-proximal processing

The nuclear cap–binding complex (CBC) stimulates RNA maturation, but the mechanistic basis is not well understood. In vitro reconstitution experiments combined with functional analyses have revealed a new CBC complex containing ARS2, a major effector of CBC. ARS2 links the cap to 3'-end maturation for several RNA families, thus favoring the production of short RNAs. The nuclear cap–binding complex (CBC) stimulates multiple steps in several RNA maturation pathways, but how it functions in humans is incompletely understood. For small, capped RNAs such as pre-snRNAs, the CBC recruits PHAX. Here, we identify the CBCAP complex, composed of CBC, ARS2 and PHAX, and show that both CBCAP and CBC–ARS2 complexes can be reconstituted from recombinant proteins. ARS2 stimulates PHAX binding to the CBC and snRNA 3′-end processing, thereby coupling maturation with export. In vivo, CBC and ARS2 bind similar capped noncoding and coding RNAs and stimulate their 3′-end processing. The strongest effects are for cap-proximal polyadenylation sites, and this favors premature transcription termination. ARS2 functions partly through the mRNA 3′-end cleavage factor CLP1, which binds RNA Polymerase II through PCF11. ARS2 is thus a major CBC effector that stimulates functional and cryptic 3′-end processing sites.