RNA G-Quadruplexes in the model plant species Arabidopsis thaliana: prevalence and possible functional roles

Mullen, Melissa A.; Olson, Kalee; Dallaire, Paul; Major, François; Assmann, Sarah M.; Bevilacqua, Philip C.

doi:10.1093/nar/gkq804

Cited by 90 publications

(102 citation statements)

References 101 publications

(128 reference statements)

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“…The human genome has a PQS density of 0.13/Kb [10] and the highest PQS density reported in literature for any organism is 0.19/Kb, for the mouse genome [25]. Interestingly, in our study we found PQS densities as high as 1.037/Kb (Fig.…”

Section: Resultssupporting

confidence: 61%

Genome-wide analysis of G-quadruplexes in herpesvirus genomes

et al. 2016

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Background: G-quadruplexes are increasingly recognized as regulatory elements in human, animal, bacterial and plant genomes. The presence and function of G-quadruplexes are not well studied among herpesviruses; in particular, there are no systematic genome-wide analysis of these important secondary structures in herpesvirus genomes.Results: We performed genome-wide analysis of putative quadruplex sequences (PQS) in human herpesviruses. We found unusually high PQS densities among human herpesviruses. PQS are enriched in the repeat regions and regulatory regions of human herpesviruses. Interestingly, PQS densities are higher in regulatory regions of immediate early genes compared to early and late genes in most herpesviruses. In addition, the majority of genes functionally conserved across human herpesviruses contain one or more PQS within the regulatory regions. We also describe the existence of unique intramolecular PQS repeats or repetitive G-quadruplex motifs in herpesviruses. Functional studies confirm a role for G-quadruplexes in regulating the gene expression of human herpesviruses. Conclusion: The pervasiveness of PQS, their enrichment and conservation at specific genomic locations suggest that these structural entities may represent a novel class of functional elements in herpesviruses. Our findings provide the necessary framework for studies on the biological role of G-quadruplexes in herpesviruses.

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Section: Resultssupporting

confidence: 61%

Genome-wide analysis of G-quadruplexes in herpesvirus genomes

et al. 2016

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“…1A, top left). The genomes of humans and many other eukaryotes are replete with putative G4-forming sequences, and pronounced, conserved patterns have been observed in their distribution, suggesting that Gquadruplex structures form at least transiently in cells and perform conserved functions (2)(3)(4)(5)(6). Supporting this hypothesis, G4s have been detected in cells for both DNA and RNA (7)(8)(9)(10)(11).…”

Section: ___________________________________mentioning

confidence: 91%

The G-quadruplex (G4) resolvase DHX36 efficiently and specifically disrupts DNA G4s via a translocation-based helicase mechanism

Yangyuoru

Bradburn

et al. 2018

Journal of Biological Chemistry

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Single-stranded DNA (ssDNA) and RNA regions that include at least four closely spaced runs of three or more consecutive guanosines strongly tend to fold into stable G-quadruplexes (G4s). G4s play key roles as DNA regulatory sites and as kinetic traps that can inhibit biological processes, but how G4s are regulated in cells remains largely unknown. Here, we developed a kinetic framework for G4 disruption by DEAH-box helicase 36 (DHX36), the dominant G4 resolvase in human cells. Using tetramolecular DNA and RNA G4s with four to six G-quartets, we found that DHX36-mediated disruption is highly efficient, with rates that depend on G4 length under saturating conditions (k cat ) but not under subsaturating conditions (k cat /K M ). These results suggest that a step during G4 disruption limits the k cat value and that DHX36 binding limits k cat /K M . Similar results were obtained for unimolecular DNA G4s. DHX36 activity depended on a 3′ ssDNA extension and was blocked by a polyethylene glycol linker, indicating that DHX36 loads onto the extension and translocates 3′-5′ toward the G4. DHX36 unwound dsDNA poorly compared with G4s of comparable intrinsic lifetime. Interestingly, we observed that DHX36 has striking 3′-extension sequence preferences that differ for G4 disruption and dsDNA unwinding, most likely arising from differences in the rate-limiting step for the two activities. Our results indicate that DHX36 disrupts G4s with a conventional helicase mechanism that is tuned for great efficiency and specificity for G4s. The dependence of DHX36 on the 3′-extension sequence suggests that the extent of formation of genomic G4s may not track directly with G4 stability. ___________________________________Single-stranded DNA and RNA segments that include at least four closely-spaced runs of three or more consecutive guanosine nucleotides have a strong intrinsic propensity to fold into stable G-quadruplex structures (G4s) (1) (Fig. 1A, top left). The genomes of humans and many other eukaryotes are replete with putative G4-forming sequences, and pronounced, conserved patterns have been observed in their distribution, suggesting that Gquadruplex structures form at least transiently in cells and perform conserved functions (2-6). Supporting this hypothesis, G4s have been detected in cells for both .To function as regulatory elements, G4s must be folded and disrupted in a regulated way. In addition, processes that require single-stranded DNA or RNA, such as replication and translation, require that G4s be temporarily disrupted. The high stability and long intrinsic lifetime of G4s suggest Mechanism of G4 disruption by DHX362 that their efficient disruption requires the activity of ATP-dependent enzymes such as helicases.Supporting this view, incorporation of sequences predicted to form particularly stable G4s leads to genetic instability in yeast, suggesting that these G4 structures are not processed efficiently and pose blocks to replication (12). Indeed, several helicases have been shown to possess G4 disruption acti...

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“…The single stranded nature of RNA is also thought to increase the likelihood of these structures forming in vivo. Increasing the number of G-tetrads [47,49,50] and shortening loop length [45,48] leads to the formation of more stable structures with a lower dependence on monovalent cations such as K + [47]. Unsurprisingly, the predicted prevalence of PQS within 5 -UTRs depends largely on the sequence parameters imposed on the computational search.…”

Section: A Role Of Eif4a Activity In Unwinding G-quadruplex Structurementioning

confidence: 99%

“…Unsurprisingly, if these parameters are relaxed to allow PQS with only two stacks of G-tetrads and/or longer loop lengths, many more PQS would be identified. However, although G-quadruplexes with just two stacks of G-tetrads are able to form under the correct conditions [24,49,50], the structural preferences of CGG repeats remains under debate. Malgowska et al [51] investigated G-quadruplex formation for CGG, AGG and UGG trinucleotide repeats in various conditions using multiple techniques.…”

Section: A Role Of Eif4a Activity In Unwinding G-quadruplex Structurementioning

confidence: 99%

“…This polymorphic nature of CGG repeats could therefore be a crucial layer of regulation, allowing these structures to only form in certain conditions such as cellular stress. For example, Mullen et al [50,52] propose that in plants, these two stacked G-quadruplex structures may only form under conditions of drought, in which levels of intracellular K + ions increase.…”

Section: A Role Of Eif4a Activity In Unwinding G-quadruplex Structurementioning

confidence: 99%

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Translational dysregulation in cancer: eIF4A isoforms and sequence determinants of eIF4A dependence

Raza

Waldron

Quesne

2015

Biochemical Society Transactions

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The malignant phenotype is largely the consequence of dysregulated gene expression. Transformed cells depend upon not just a global increase in protein synthesis but an altered translational landscape in which pro-oncogenic mRNAs are translationally up-regulated. Such mRNAs have been shown to possess longer and more structured 5'-UTRs requiring high levels of eukaryotic initiation factor 4A (eIF4A) helicase activity for efficient translation. As such there is a developing focus on targeting eIF4A as a cancer therapy. In order for such treatments to be successful, we must develop a detailed understanding of the mechanisms which make specific mRNAs more dependent on eIF4A activity than others. It is also crucial to fully characterize the potentially distinct roles of eIF4A1 and eIF4A2, which until recently were thought to be functionally interchangeable. This review will highlight the recent advances made in this field that address these issues.

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RNA G-Quadruplexes in the model plant species Arabidopsis thaliana: prevalence and possible functional roles

Cited by 90 publications

References 101 publications

Genome-wide analysis of G-quadruplexes in herpesvirus genomes

Genome-wide analysis of G-quadruplexes in herpesvirus genomes

The G-quadruplex (G4) resolvase DHX36 efficiently and specifically disrupts DNA G4s via a translocation-based helicase mechanism

Translational dysregulation in cancer: eIF4A isoforms and sequence determinants of eIF4A dependence

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