Mediator regulates transcriptional termination through cross-talk with pre-mRNA 3' end processing factors. Chengjiang Lu et al

Beyond its function in transcription initiation, the Mediator complex coordinates the processes of transcription elongation and mRNA splicing. Here, we report that Mediator associates with CPSF complex in the pre-mRNA 3’ end processing machinery, partially through the MED23-FIP1 connection, for control of transcription termination. We observed the physical association and coordinated occupancy of MED23 and FIP1 at both promoter and terminator regions, and MED23 directly binds to hundreds of 3’ mRNAs. Depleting MED23 or FIP1 or overexpressing the intrinsically disordered regions (IDRs) of FIP1 attenuated the Mediator-CPSF association and reduced the genomic occupancy of CPSF. Consequently, MED23 deficiency led to hundreds of readthrough events and fusion transcripts, and the 3’ RNA binding of MED23 is critical for the transcription termination regulation. Moreover, integrative analysis revealed that MED23 deficiency contributed to readthrough in breast cancers, thus providing new molecular insights into carcinogenesis.