Integrator is a genome-wide attenuator of non-productive transcription

Integrator enforces the fidelity of transcriptional termination at protein-coding genes

“…Notably, we observed increased genomic occupancy of CPA components at the 3′ end of IRT genes, suggesting that, in the absence of INTS11, recruitment of the CPA machinery may compensate for the lack of 3′ end processing and sustains the recruitment of subsequent termination factors. A recent study suggests that Integrator and CPA machinery can occupy similar regions of DNA and cooperate to terminate human lncRNA transcription ( 30 ). Our results point to cooperative roles for the Integrator complex and CPA machinery in the processing of IRT genes, thereby extending this model to protein-coding genes ( Fig.…”

“…Previous work demonstrates that Integrator mediates the activation of immediate early genes, thereby controlling the transcriptional output of growth factor signaling (22,26,27). Notably, recent studies have shown that the catalytic activity of Integrator regulates elongation at coding genes by premature termination of transcripts associated with paused RNAPII (28)(29)(30)(31).…”

Rapid factor depletion highlights intricacies of nucleoplasmic RNA degradation

“…NEXT- and PAXT-sensitive RNAs have been thoroughly characterized ( 19 , 22 , 25–28 ). Generally, the NEXT complex targets RNAs with unprotected and nonadenylated (pA − ) 3′ ends, exemplified by transcripts produced by the aforementioned PROMPT and eRNA loci as well as the large amount of TSS-proximal transcription termination at RNAPII transcription units (TUs) ( 29 ). Furthermore, the biogenesis of snoRNAs generates a sizable number of pA − and NEXT-sensitive processing intermediates ( 24 ).…”

“…While information about 5′–3′ trimming mechanisms is limited ( 30 , 32 , 33 ), some lines of evidence have implicated the RNA exosome and NEXT in the 3′–5′ exonucleolysis of snoRNA-hosting introns, and possibly also regular introns ( 24 , 34 , 35 ). In contrast to this vast production of pA − ends, polyadenylated (pA + ) RNA 3′ ends mostly originate from cleavage and polyadenylation-dependent processing ( 29 , 36 ). If the resulting transcript is not rapidly exported to the cytoplasm, such pA + 3′ ends can be subject to PAXT-mediated degradation, which targets many lncRNAs, PROMPTs, eRNAs, ptRNAs and a subset of mRNAs ( 19 , 22 , 25–27 , 37 ).…”

Structural basis of INTAC-regulated transcription

“…Integrator complex 13,14 functions as an RNA endonuclease to cleave different classes of RNAs [15][16][17][18][19] . More recent studies discovered that Integrator is enriched in the proximity of RNA promoters 20 and can associate with paused Pol II bound by DSIF and NELF 21,22 to trigger PTT and repress gene activity 18,[23][24][25][26][27][28] . We have recently found that Integrator associates with protein phosphatase 2A core enzyme (PP2A-AC) and dephosphorylates the C-terminal domain (CTD) of Pol II and determined the structure of Integrator-containing PP2A-AC (termed INTAC), showing how the RNA nuclease and protein phosphatase are organized in the INTAC complex 7 .…”