The Integrator complex controls the termination of transcription at diverse classes of gene targets

• Published in: Cell research Vol. 25; no. 3; pp. 288 - 305
• Main Authors: Skaar, Jeffrey R, Ferris, Andrea L, Wu, Xiaolin, Saraf, Anita, Khanna, Kum Kum, Florens, Laurence, Washburn, Michael P, Hughes, Stephen H, Pagano, Michele
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.03.2015
• Subjects: Cell Line, Tumor; DNA-Binding Proteins - antagonists & inhibitors; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; DNA损伤; HEK293 Cells; HeLa Cells; Histones - biosynthesis; Histones - genetics; Human immunodeficiency virus; Humans; Integrator; Mitochondrial Proteins - antagonists & inhibitors; Mitochondrial Proteins - genetics; Mitochondrial Proteins - metabolism; Nuclear Proteins - genetics; Original; Polyadenylation - genetics; Promoter Regions, Genetic - genetics; RNA Polymerase II - genetics; RNA Polymerase II - metabolism; RNA Processing, Post-Transcriptional; RNA, Small Nuclear - genetics; RNA, Small Nuclear - metabolism; RNA聚合酶; Transcription Factors - genetics; Transcription Termination, Genetic - physiology; Transcriptional Elongation Factors - genetics; 同类; 控制; 积分器; 转录物; 靶基因
• ISSN: 1001-0602; 1748-7838; 1748-7838
• DOI: 10.1038/cr.2015.19

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-se- quencing （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 Inte- grator negatively regulates expression of genes whose transcripts are normally polyadenylated. Integrator recruit- ment to all three gene classes is DSIF-dependent, suggesting that Integrator functions as a termination complex at DSIF-dependent RNA Polymerase II pause sites.