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

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 like 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 as well as snRNAs 3'-end processing, hereby coupling maturation with export. In vivo, CBC and Ars2 bind similar capped non-coding and coding RNAs, and stimulate their 3’-end processing. Strongest effects are displayed for cap-proximal polyadenylation sites, thereby favoring premature transcription termination. Ars2 functions in part 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. In total 12 samples; 4 control IP, 2 Flag- Ars2 IP and 2 Flag-CBP20 IP; 2 control FFL siRNA and 2 siRNA Ars2