Integrator-Dependent and Allosteric/Intrinsic Mechanisms Ensure Efficient Termination of snRNA Transcription

Davidson, Lee; Francis, Laura; Eaton, Joshua D.; West, Steven

doi:10.1016/j.celrep.2020.108319

Cited by 29 publications

(27 citation statements)

References 55 publications

(61 reference statements)

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“…ZC3H4 has some functions in common with the Integrator complex, being metazoanspecific and relevant to the metabolism of unstable non-coding RNA (Lai et al, 2015;Mendoza-Figueroa et al, 2020;Nojima et al, 2018). We previously published chromatin RNAseq derived from cells RNAi depleted of the Integrator backbone component INTS1 (Davidson et al, 2020). Metagene analysis of this data at protein-coding genes shows a mild effect of Integrator depletion over PROMPT regions ( Figure 4A).…”

Section: Comparison Of Zc3h4 and Integrator Effectsmentioning

confidence: 99%

“…The Integrator complex aids termination of many non-coding transcripts, with the archetypal example being snRNAs (Baillat et al, 2005;Davidson et al, 2020;O'Reilly et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

“…However, INTS11 activity does not precede XRN2 effects (Eaton et al, 2018). Moreover, while CPSF73 is indispensable for termination at protein-coding genes, a milder effect is seen at snRNAs when Integrator is depleted (Davidson et al, 2020). Integrator is also implicated in the termination of promoter upstream transcripts (PROMPTs) and enhancer RNAs (eRNAs) (Beckedorff et al, 2020;Lai et al, 2015;Nojima et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

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ZC3H4 restricts non-coding transcription in human cells

Estell

Davidson

Steketee

et al. 2021

Preprint

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The human genome encodes thousands of non-coding RNAs. Many of these terminate early and are then rapidly degraded, but how their transcription is restricted is poorly understood. In a screen for protein-coding gene termination factors, we identified ZC3H4. However, its depletion causes upregulation and extension of hundreds of unstable transcripts, particularly antisense RNAs and those transcribed from so-called super-enhancers. These loci are occupied by ZC3H4, suggesting that it directly functions in their transcription. Consistently, engineered tethering of ZC3H4 to reporter RNA promotes its degradation by the exosome. ZC3H4 is metazoan-specific - interesting when considering its impact on enhancer RNAs that are absent in single-celled organisms. Finally, ZC3H4 loss causes a substantial reduction in cell proliferation, highlighting its overall importance. In summary, we identify ZC3H4 as a factor that plays an important role in restricting non-coding transcription in multi-cellular organisms.

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Section: Comparison Of Zc3h4 and Integrator Effectsmentioning

confidence: 99%

“…The Integrator complex aids termination of many non-coding transcripts, with the archetypal example being snRNAs (Baillat et al, 2005;Davidson et al, 2020;O'Reilly et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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ZC3H4 restricts non-coding transcription in human cells

Estell

Davidson

Steketee

et al. 2021

Preprint

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“…The Integrator was discovered as a factor required for 3′ end processing of metazoan snRNAs ( Baillat et al., 2005 ), which critically depend on snRNA promoters driving transcription ( Hernandez and Weiner, 1986 ; Lobo and Hernandez, 1989 ), and the Integrator is believed to couple both processes ( Egloff et al., 2007 ). More recent studies suggest that transcription termination of human snRNA genes may also occur in an Integrator-independent manner ( Davidson et al., 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Structure of the catalytic core of the Integrator complex

Pfleiderer

Galej

2021

Molecular Cell

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Summary The Integrator is a specialized 3′ end-processing complex involved in cleavage and transcription termination of a subset of nascent RNA polymerase II transcripts, including small nuclear RNAs (snRNAs). We provide evidence of the modular nature of the Integrator complex by biochemically characterizing its two subcomplexes, INTS5/8 and INTS10/13/14. Using cryoelectron microscopy (cryo-EM), we determined a 3.5-Å-resolution structure of the INTS4/9/11 ternary complex, which constitutes Integrator’s catalytic core. Our structure reveals the spatial organization of the catalytic nuclease INTS11, bound to its catalytically impaired homolog INTS9 via several interdependent interfaces. INTS4, a helical repeat protein, plays a key role in stabilizing nuclease domains and other components. In this assembly, all three proteins form a composite electropositive groove, suggesting a putative RNA binding path within the complex. Comparison with other 3′ end-processing machineries points to distinct features and a unique architecture of the Integrator’s catalytic module.

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“…The Integrator complex aids termination of many non-coding transcripts, with the archetypal example being snRNAs (Baillat et al, 2005;Davidson et al, 2020;O'Reilly et al, 2014). Integrator is also implicated in the termination of promoter upstream transcripts (PROMPTs) and enhancer RNAs (eRNAs) (Beckedorff et al, 2020;Lai et al, 2015;Nojima et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

ZC3H4 restricts non-coding transcription in human cells

Estell

Davidson

Steketee

et al. 2021

eLife

Self Cite

View full text Add to dashboard Cite

The human genome encodes thousands of non-coding RNAs. Many of these terminate early and are then rapidly degraded, but how their transcription is restricted is poorly understood. In a screen for protein-coding gene transcriptional termination factors, we identified ZC3H4. Its depletion causes upregulation and extension of hundreds of unstable transcripts, particularly antisense RNAs and those transcribed from so-called super-enhancers. These loci are occupied by ZC3H4, suggesting that it directly functions in their transcription. Consistently, engineered tethering of ZC3H4 to reporter RNA promotes its degradation by the exosome. ZC3H4 is predominantly metazoan - interesting when considering its impact on enhancer RNAs that are less prominent in single-celled organisms. Finally, ZC3H4 loss causes a substantial reduction in cell proliferation, highlighting its overall importance. In summary, we identify ZC3H4 as playing an important role in restricting non-coding transcription in multi-cellular organisms.

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Integrator-Dependent and Allosteric/Intrinsic Mechanisms Ensure Efficient Termination of snRNA Transcription

Abstract: Highlights d Integrator-dependent and-independent mechanisms terminate snRNA transcription d Integrator-independent termination is allosteric/intrinsic in nature d Sites of allosteric/intrinsic termination often coincide with Truns

Cited by 29 publications

References 55 publications

ZC3H4 restricts non-coding transcription in human cells

ZC3H4 restricts non-coding transcription in human cells

Structure of the catalytic core of the Integrator complex

ZC3H4 restricts non-coding transcription in human cells

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