@article{a20c049ce27c48febdb0813311693d5a,
title = "Integrator Recruits Protein Phosphatase 2A to Prevent Pause Release and Facilitate Transcription Termination",
abstract = "Efficient release of promoter-proximally paused RNA Pol II into productive elongation is essential for gene expression. Recently, we reported that the Integrator complex can bind paused RNA Pol II and drive premature transcription termination, potently attenuating the activity of target genes. Premature termination requires RNA cleavage by the endonuclease subunit of Integrator, but the roles of other Integrator subunits in gene regulation have yet to be elucidated. Here we report that Integrator subunit 8 (IntS8) is critical for transcription repression and required for association with protein phosphatase 2A (PP2A). We find that Integrator-bound PP2A dephosphorylates the RNA Pol II C-terminal domain and Spt5, preventing the transition to productive elongation. Thus, blocking PP2A association with Integrator stimulates pause release and gene activity. These results reveal a second catalytic function associated with Integrator-mediated transcription termination and indicate that control of productive elongation involves active competition between transcriptional kinases and phosphatases.",
keywords = "Integrator, paused RNA Pol II, phosphatase, transcription regulation, transcription termination",
author = "Kai-Lieh Huang and David Jee and Stein, {Chad B.} and Elrod, {Nathan D.} and Telmo Henriques and Mascibroda, {Lauren G.} and David Baillat and Russell, {William K.} and Karen Adelman and Eric Wagner",
note = "Funding Information: We thank the BPF Next-Gen Sequencing Core Facility at Harvard Medical School and members of the Wagner and Adelman labs for helpful discussions. This work was supported by The Cancer Prevention Research Institute of Texas (CPRIT) grant RP170593 (to K.-L.H.), National Institutes of Health grant R01-GM134539 (to K.A. and E.J.W.), the Intramural Research Program of the NIH and National Institute of Environmental Health Sciences ( Z01ES101987 to K.A.), and Welch Foundation grant H-1889-20180324 (to The University of Texas Medical Branch at Galveston [E.J.W.]). The UTMB Mass Spectrometry Facility is supported in part by CPRIT grant RP190682 (to W.K.R.). Funding Information: We thank the BPF Next-Gen Sequencing Core Facility at Harvard Medical School and members of the Wagner and Adelman labs for helpful discussions. This work was supported by The Cancer Prevention Research Institute of Texas (CPRIT) grant RP170593 (to K.-L.H.), National Institutes of Health grant R01-GM134539 (to K.A. and E.J.W.), the Intramural Research Program of the NIH and National Institute of Environmental Health Sciences (Z01ES101987 to K.A.), and Welch Foundation grant H-1889-20180324 (to The University of Texas Medical Branch at Galveston [E.J.W.]). The UTMB Mass Spectrometry Facility is supported in part by CPRIT grant RP190682 (to W.K.R.). K.-L.H. D.J. N.D.E. K.A. and E.J.W. designed and performed the RNA-seq and PRO-seq experiments. C.B.S. N.D.E. and T.H. analyzed the genomics datasets. K.-L.H. and D.B. designed and performed biochemical experiments. W.K.R. conducted mass spectrometry. K.-L.H. and L.G.M. conducted the yeast two-hybrid experiments. K.A. and E.J.W. wrote the manuscript with input from all authors. K.A. and E.J.W. consult for Syros Pharmaceuticals, and K.A. is on the scientific advisory board of CAMP4 Therapeutics. Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",
year = "2020",
month = oct,
day = "15",
doi = "10.1016/j.molcel.2020.08.016",
language = "English (US)",
volume = "80",
pages = "345--358.e9",
journal = "Molecular cell",
issn = "1097-2765",
publisher = "Cell Press",
number = "2",
}