Crosstalk of promoter and terminator during RNA polymerase II transcription cycle

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Viral infections and the harm they cause to their host are a perpetual threat to living organisms. Pathogenesis and subsequent spread of infection requires replication of the viral genome and expression of structural and non-structural proteins of the virus. Generally, viruses use transcription and translation machinery of the host cell to achieve this objective. The viral genome encodes transcriptional regulators that alter the expression of viral and host genes by manipulating initiation and termination steps of transcription. The regulation of the initiation step is often through interactions of viral factors with gene specific factors as well as general transcription factors (GTFs). Among the GTFs, TFIIB (Transcription Factor IIB) is a frequent target during viral pathogenesis. TFIIB is utilized by a plethora of viruses including human immunodeficiency virus, herpes simplex virus, vaccinia virus, Thogoto virus, hepatitis virus, Epstein-Barr virus and gammaherpesviruses to alter gene expression. A number of viral transcriptional regulators exhibit a direct interaction with host TFIIB in order to accomplish expression of their genes and to repress host transcription. Some viruses have evolved proteins with a three-dimensional structure very similar to TFIIB, demonstrating the importance of TFIIB for viral persistence. Upon viral infection, host transcription is selectively altered with viral transcription benefitting. The nature of viral utilization of TFIIB for expression of its own genes, along with selective repression of host antiviral genes and downregulation of general host transcription, makes TFIIB a potential candidate for antiviral therapies.

Section: Discussionmentioning

confidence: 99%

Critical Involvement of TFIIB in Viral Pathogenesis

O’Brien

Ansari

2021

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“…The classical view of transcriptional regulation by cis-acting regulatory sequences and trans-acting protein factors has undergone radical changes due to research carried out during the last few decades (Papantonis and Cook, 2010;Ansari, 2019;Al-Husini et al, 2020). Genome topology or chromatin conformations formed by enhancer-promoter interactions and promoter-terminator interactions have been found to play a crucial role in regulation of transcription (Misteli, 2007).…”

Section: Intron-dependent Looped Gene Architecture Facilitates Enhancement Of Transcriptionmentioning

confidence: 99%

“…The physical interaction of the promoter and terminator regions of a gene during transcription results in the formation of a looped gene architecture (Ansari and Hampsey, 2005). Such gene loops are formed in an activator-dependent manner and have been observed in yeast as well as in higher eukaryotes (reviewed in Al- Husini et al, 2020). Activator-dependent gene looping has been shown to enhance transcription by facilitating direct transfer of polymerase from the terminator to the promoter for reinitiation, and by enhancing promoter directionality (Tan-Wong et al, 2012;Al Husini et al, 2013).…”

Section: Intron-dependent Looped Gene Architecture Facilitates Enhancement Of Transcriptionmentioning

confidence: 99%

“…How the presence of an intron facilitates gene loop formation, however, is not yet clear. It has been proposed that the interaction of a 5 splice site with the promoter and of a 3 splice site with terminator bring the two ends of a gene in close physical proximity and facilitate the promoterterminator contact (Al- Husini et al, 2020). Only a splicingcompetent intron facilitates gene loop formation (Moabbi et al, 2012;Agarwal and Ansari, 2016).…”

Section: Intron-dependent Looped Gene Architecture Facilitates Enhancement Of Transcriptionmentioning

confidence: 99%

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Gene Architecture Facilitates Intron-Mediated Enhancement of Transcription

Dwyer

Agarwal

Pile

et al. 2021

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Introns impact several vital aspects of eukaryotic organisms like proteomic plasticity, genomic stability, stress response and gene expression. A role for introns in the regulation of gene expression at the level of transcription has been known for more than thirty years. The molecular basis underlying the phenomenon, however, is still not entirely clear. An important clue came from studies performed in budding yeast that indicate that the presence of an intron within a gene results in formation of a multi-looped gene architecture. When looping is defective, these interactions are abolished, and there is no enhancement of transcription despite normal splicing. In this review, we highlight several potential mechanisms through which looping interactions may enhance transcription. The promoter-5′ splice site interaction can facilitate initiation of transcription, the terminator-3′ splice site interaction can enable efficient termination of transcription, while the promoter-terminator interaction can enhance promoter directionality and expedite reinitiation of transcription. Like yeast, mammalian genes also exhibit an intragenic interaction of the promoter with the gene body, especially exons. Such promoter-exon interactions may be responsible for splicing-dependent transcriptional regulation. Thus, the splicing-facilitated changes in gene architecture may play a critical role in regulation of transcription in yeast as well as in higher eukaryotes.

“…We recently examined the mechanism of intron-mediated enhancement effect in budding yeast and found that a promoter-proximal intron results in the formation of a unique looped gene architecture (Moabbi et al, 2012;Agarwal and Ansari, 2016;Dwyer et al, 2021). We showed that the gene loop facilitated the recruitment of termination factors near the promoter-proximal region, and these termination factors inhibited upstream antisense RNA (uaRNA) synthesis, thereby conferring directionality to the promoter (Agarwal and Ansari, 2016;Al Husini et al, 2020). This results in enhanced transcription of mRNA.…”

Section: Introductionmentioning

confidence: 99%

Proximity to the Promoter and Terminator Regions Regulates the Transcription Enhancement Potential of an Intron

Dwyer

Agarwal

Gega

et al. 2021

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An evolutionarily conserved feature of introns is their ability to enhance expression of genes that harbor them. Introns have been shown to regulate gene expression at the transcription and post-transcription level. The general perception is that a promoter-proximal intron is most efficient in enhancing gene expression and the effect diminishes with the increase in distance from the promoter. Here we show that the intron regains its positive influence on gene expression when in proximity to the terminator. We inserted ACT1 intron into different positions within IMD4 and INO1 genes. Transcription Run-On (TRO) analysis revealed that the transcription of both IMD4 and INO1 was maximal in constructs with a promoter-proximal intron and decreased with the increase in distance of the intron from the promoter. However, activation was partially restored when the intron was placed close to the terminator. We previously demonstrated that the promoter-proximal intron stimulates transcription by affecting promoter directionality through gene looping-mediated recruitment of termination factors in the vicinity of the promoter region. Here we show that the terminator-proximal intron also enhances promoter directionality and results in compact gene architecture with the promoter and terminator regions in close physical proximity. Furthermore, we show that both the promoter and terminator-proximal introns facilitate assembly or stabilization of the preinitiation complex (PIC) on the promoter. On the basis of these findings, we propose that proximity to both the promoter and the terminator regions affects the transcription regulatory potential of an intron, and the terminator-proximal intron enhances transcription by affecting both the assembly of preinitiation complex and promoter directionality.