Integrator is a key component of human telomerase RNA biogenesis

Rubtsova, Maria P.; Vasilkova, Daria; Moshareva, Maria; Malyavko, Alexander N.; Meerson, Mark; Zatsepin, Timofei S.; Naraykina, Yulia; Beletsky, Alexey V.; Ravin, Nikolai V.; Донцова, О. А.

doi:10.1038/s41598-018-38297-6

Cited by 47 publications

(32 citation statements)

References 35 publications

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“…In addition to cleaving MtnA transcripts, Integrator cleaves multiple other RNA classes in metazoan cells, including enhancer RNAs (Lai et al 2015), snRNAs (Baillat et al 2005), telomerase RNA (Rubtsova et al 2019), and some herpesvirus microRNA precursors (Cazalla et Page 15 al. 2011;Xie et al 2015).…”

Section: Discussionmentioning

confidence: 99%

The Integrator complex cleaves nascent mRNAs to attenuate transcription

Tatomer

Elrod

Liang

et al. 2019

Preprint

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words)Cellular homeostasis requires transcriptional outputs to be coordinated, and many events post transcription initiation can dictate the levels and functions of mature transcripts. To systematically identify regulators of inducible gene expression, we performed high-throughputRNAi screening of the Drosophila Metallothionein A (MtnA) promoter. This revealed that the Integrator complex, which has a well-established role in 3' end processing of small nuclear RNAs (snRNAs), attenuates MtnA transcription during copper stress. Integrator complex subunit 11 (IntS11) endonucleolytically cleaves MtnA transcripts, resulting in premature transcription termination and degradation of the nascent RNAs by the RNA exosome, a complex also identified in the screen. Using RNA-seq, we then identified >400 additional Drosophila proteincoding genes whose expression increases upon Integrator depletion. We focused on a subset of these genes and confirmed that Integrator is bound to their 5' ends and negatively regulates their transcription via IntS11 endonuclease activity. Many non-catalytic Integrator subunits, which are largely dispensable for snRNA processing, also have regulatory roles at these protein-coding genes, possibly by controlling Integrator recruitment or RNA polymerase II dynamics.Altogether, our results suggest that attenuation via Integrator cleavage limits production of many full-length mRNAs, allowing precise control of transcription outputs.

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Section: Discussionmentioning

confidence: 99%

The Integrator complex cleaves nascent mRNAs to attenuate transcription

Tatomer

Elrod

Liang

et al. 2019

Preprint

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“…The Integrator CM, through the activity of INTS11, has been shown to be essential to cleave the 3' ends of a variety of noncoding RNA and nascent mRNA of protein-coding genes with paused RNAPII. This catalytic activity thus serves as a key functional component of Integrator-mediated transcriptional repression and for the biogenesis of noncoding RNA 34,35,36,37,38 .…”

Section: Introductionmentioning

confidence: 99%

INTS13Mutations Causing a Developmental Ciliopathy Disrupt Integrator Complex Assembly

Shboul

et al. 2020

Preprint

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Oral-facial-digital syndromes (OFD) are a heterogeneous group of congenital disorders characterized by malformations of the face and oral cavity, and digit anomalies. To date, mutations in 12 ciliary-related genes have been identified that cause several types of OFD, suggesting that OFDs constitute a subgroup of developmental ciliopathies. Through homozygosity mapping and exome sequencing of two families with variable OFD type 2, we identified distinct germline mutations in INTS13, a subunit of the Integrator complex. This 14-component complex associates with RNAPII and can cleave nascent RNA to modulate gene expression. We determined that INTS13 utilizes a discrete domain within its C-terminus to bind the Integrator cleavage module, which is disrupted by the identified germline INTS13 mutations. Depletion of INTS13 disrupts ciliogenesis in human cultured cells and causes dysregulation of a broad collection of ciliary genes. Accordingly, its knockdown in Xenopus embryos lead to motile cilia anomalies. Altogether, we show that mutations in INTS13 cause an autosomal recessive ciliopathy, which reveals key interactions within Integrator components.

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“…INT was first identified as the long sought-after 3′-end processing complex for uridine-rich small nuclear RNAs (UsnRNAs), which form the center of the splicing machinery 4 . Later, it was also shown to cleave nascent transcripts of enhancer RNAs (eRNAs), which are transcriptional regulators in metazoans 5 , telomerase RNA 6 , a simian viral micro-RNA precursor (pre-miR HSUR4) 7 and spliced leader snRNAs in nematodes 8 .…”

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confidence: 99%

INTS10–INTS13–INTS14 form a functional module of Integrator that binds nucleic acids and the cleavage module

et al. 2020

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The Integrator complex processes 3′-ends of spliceosomal small nuclear RNAs (snRNAs). Furthermore, it regulates transcription of protein coding genes by terminating transcription after unstable pausing. The molecular basis for Integrator's functions remains obscure. Here, we show that INTS10, Asunder/INTS13 and INTS14 form a separable, functional Integrator module. The structure of INTS13-INTS14 reveals a strongly entwined complex with a unique chain interlink. Unexpected structural homology to the Ku70-Ku80 DNA repair complex suggests nucleic acid affinity. Indeed, the module displays affinity for DNA and RNA but prefers RNA hairpins. While the module plays an accessory role in snRNA maturation, it has a stronger influence on transcription termination after pausing. Asunder/INTS13 directly binds Integrator's cleavage module via a conserved C-terminal motif that is involved in snRNA processing and required for spermatogenesis. Collectively, our data establish INTS10-INTS13-INTS14 as a nucleic acid-binding module and suggest that it brings cleavage module and target transcripts into proximity.

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Integrator is a key component of human telomerase RNA biogenesis

Cited by 47 publications

References 35 publications

The Integrator complex cleaves nascent mRNAs to attenuate transcription

The Integrator complex cleaves nascent mRNAs to attenuate transcription

INTS13Mutations Causing a Developmental Ciliopathy Disrupt Integrator Complex Assembly

INTS10–INTS13–INTS14 form a functional module of Integrator that binds nucleic acids and the cleavage module

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