title: The Integrator complex controls the termination of transcription at diverse classes of gene targets.
abstract: Complexes containing INTS3 and either NABP1 or NABP2 were initially characterized in DNA damage responses, but their biochemical function remained unknown. Using affinity purifications and HIV Integration targeting-sequencing (HIT-Seq), we find that these complexes are part of the Integrator complex, which binds RNA Polymerase II and regulates specific target genes. Integrator cleaves snRNAs as part of their processing to their mature form in a mechanism that is intimately coupled with transcription termination. However, HIT-Seq reveals that Integrator also binds to the 3' end of replication-dependent histones and promoter proximal regions of genes with polyadenylated transcripts. Depletion of Integrator subunits results in transcription termination failure, disruption of histone mRNA processing, and polyadenylation of snRNAs and histone mRNAs. Furthermore, promoter proximal binding of Integrator negatively regulates expression of genes whose transcripts are normally polyadenylated. Integrator recruitment to all three gene classes is DSIF-dependent, suggesting that Integrator functions as a termination complex at DSIF-dependent RNA Polymerase II pause sites.
authors: Department of Pathology, Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, 522 First Avenue, New York, NY 10016, USA.
authors: Jeffrey R
authors: JR
authors: Skaar
authors: HIV Drug Resistance Program, National Cancer Institute, Frederick, MD 21702, USA.
authors: Andrea L
authors: AL
authors: Ferris
authors: Cancer Research Technology Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.
authors: Xiaolin
authors: X
authors: Wu
authors: The Stowers Institute for Medical Research, Kansas City, MO 6411, USA.
authors: Anita
authors: A
authors: Saraf
authors: QIMR Berghofer Medical Research Institute, Herston, Brisbane, Queensland 4006, Australia.
authors: Kum Kum
authors: KK
authors: Khanna
authors: The Stowers Institute for Medical Research, Kansas City, MO 6411, USA.
authors: Laurence
authors: L
authors: Florens
authors: 1] The Stowers Institute for Medical Research, Kansas City, MO 6411, USA [2] Department of Pathology and Laboratory Medicine, The University of Kansas Medical Center, Kansas City, KS 66160, USA.
authors: Michael P
authors: MP
authors: Washburn
authors: HIV Drug Resistance Program, National Cancer Institute, Frederick, MD 21702, USA.
authors: Stephen H
authors: SH
authors: Hughes
authors: 1] Department of Pathology, Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, 522 First Avenue, New York, NY 10016, USA [2] Howard Hughes Medical Institute, 522 First Avenue New York, NY 10016, USA.
authors: Michele
authors: M
authors: Pagano
mesh_terms: D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006367:HeLa Cells; D006657:Histones / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D024101:Mitochondrial Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics; D026723:Polyadenylation / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D012319:RNA Polymerase II / Q000235:genetics / Q000378:metabolism*; D012323:RNA Processing, Post-Transcriptional; D012342:RNA, Small Nuclear / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics; D061806:Transcription Termination, Genetic / Q000502:physiology*; D035602:Transcriptional Elongation Factors / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; D006657:Histones; C543505:INTS3 protein, human; C581727:JunB protein, human; D024101:Mitochondrial Proteins; D009687:Nuclear Proteins; D012342:RNA, Small Nuclear; C504091:NABP2 protein, human; C477058:SSBP2 protein, human; C112224:SUPT5H protein, human; D014157:Transcription Factors; D035602:Transcriptional Elongation Factors; D012319:RNA Polymerase II