An atypical RNA quadruplex marks RNAs as vectors for gene silencing

Roschdi, Saeed; Yan, Jenny; Nomura, Yoshinobu; Escobar, Cristian A.; Petersen, Riley J.; Bingman, C.A.; Tonelli, Marco; Vivek, Rahul; Eric, Montemayor,; Wickens, Marvin; Kennedy, Scott; Butcher, Samuel E.

doi:10.1038/s41594-022-00854-z

Cited by 30 publications

(33 citation statements)

References 56 publications

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“…Recently, another study demonstrated that GU repeats can fold into a structure termed a pUG-fold ( Roschdi et al 2022 ). pUG-folds are noncanonical parallel G4 structures with a left-handed backbone in which Us are looped out to allow the formation of three stacked G-quartets capped by a terminal U-quartet.…”

Section: Resultsmentioning

confidence: 99%

“…We first use formaldehyde RNA immunoprecipitation, followed by next-generation sequencing (fRIP-seq) on endogenous DNMT1 in two different cell lines, and find that DNMT1 interacts with many RNAs, and surprisingly, its own mRNA. Upon further analysis of RNA sequence and structure preference of DNMT1, we see a high and specific affinity for a recently discovered RNA structure called a poly-(UG)-fold (pUG-fold) ( Roschdi et al 2022 ). We also find that DNMT1 displays a general but lower affinity for a variety of other RNAs.…”

Section: Introductionmentioning

confidence: 99%

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DNMT1 inhibition by pUG-fold quadruplex RNA

Jansson-Fritzberg

Sousa

Smallegan

et al. 2022

RNA

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Aberrant DNA methylation is one of the earliest hallmarks of cancer. DNMT1 is responsible for methylating newly replicated DNA, but the precise regulation of DNMT1 to ensure faithful DNA methylation remains poorly understood. A link between RNA and chromatin-associated proteins has recently emerged, and several studies have shown that DNMT1 can be regulated by a variety of RNAs. In this study we have confirmed that human DNMT1 indeed interacts with multiple RNAs, including its own nuclear mRNA. Unexpectedly, we found that DNMT1 exhibits a strong and specific affinity for GU-rich RNAs that form a pUG-fold, a non-canonical G-quadruplex. We find that pUG-fold-capable RNAs inhibit DNMT1 activity by inhibiting binding of hemimethylated DNA, and additionally provide evidence for multiple RNA binding modes with DNMT1. Together, our data indicates that a human chromatin-associated protein binds to and is regulated by pUG-fold RNA.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

DNMT1 inhibition by pUG-fold quadruplex RNA

Jansson-Fritzberg

Sousa

Smallegan

et al. 2022

RNA

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“…The weak but characteristic lone pair–π contact is shown as a red triangle. The particular Z-geometry with sugar pointing in opposite directions is found in other structural contexts, such as, for example, the ligand binding site of the purine riboswitch (PDB: 4FE5, Batey et al 2004 ), and the core of the pUG G-quadruplex (PDB: 7MKT, Roschdi et al 2022 ). ( B ) Potential mechanisms for Z-RNA formation and stabilization in vivo.…”

Section: What Did We Learn From Studying Z-rna In Vitro?mentioning

confidence: 98%

“…Furthermore, Z-RNA geometry was observed in non-GC single-stranded regions important for function within riboswitches, ribozymes and other structured RNAs with known functions ( D'Ascenzo et al 2016 ), as well as within atypical quadruplexes ( Fig. 1 A; Roschdi et al 2022 ). These findings suggest that certain regions within cellular RNAs (i.e., alternating purine-pyrimidine sequences) could be prone to adopt Z conformations.…”

Section: What Did We Learn From Studying Z-rna In Vitro?mentioning

confidence: 99%

Z-RNA biology: a central role in the innate immune response?

Nichols

Krall

Henen

et al. 2023

RNA

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Z-RNA is a higher-energy, left-handed conformation of RNA, whose function has remained elusive. A growing body of work alludes to regulatory roles for Z-RNA in the immune response. Here, we review how Z-RNA features present in cellular RNAs —especially containing retroelements— could be recognized by a family of winged helix proteins, with an impact on host defense. We also discuss how mutations to specific Z-contacting amino acids disrupt their ability to stabilize Z-RNA, resulting in functional losses. We end by highlighting knowledge gaps in the field, which, if addressed, would significantly advance this active area of research.

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“…Thus, there generally needs to be a near even ratio of anti -p- syn to syn -p- anti steps to favorably adopt the Z-conformation, as seen in the polynucleotide d[GC] n [ 42 ] and for d(GC) n oligonucleotides where n ≥ 5 [ 43 ]. While the anti -p- syn “Z-step” has historically been seen as the defining dinucleotide of the Z-conformation [ 34 ], a recent structure of a left-handed quadruplex displays backbone conformations representing the “Z-like” syn -p- anti dinucleotide [ 45 ].…”

Section: Structural Characteristics Of the Z-conformationmentioning

confidence: 99%

Structure and Formation of Z-DNA and Z-RNA

et al. 2023

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Despite structural differences between the right-handed conformations of A-RNA and B-DNA, both nucleic acids adopt very similar, left-handed Z-conformations. In contrast to their structural similarities and sequence preferences, RNA and DNA exhibit differences in their ability to adopt the Z-conformation regarding their hydration shells, the chemical modifications that promote the Z-conformation, and the structure of junctions connecting them to right-handed segments. In this review, we highlight the structural and chemical properties of both Z-DNA and Z-RNA and delve into the potential factors that contribute to both their similarities and differences. While Z-DNA has been extensively studied, there is a gap of knowledge when it comes to Z-RNA. Where such information is lacking, we try and extend the principles of Z-DNA stability and formation to Z-RNA, considering the inherent differences of the nucleic acids.

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An atypical RNA quadruplex marks RNAs as vectors for gene silencing

Cited by 30 publications

References 56 publications

DNMT1 inhibition by pUG-fold quadruplex RNA

DNMT1 inhibition by pUG-fold quadruplex RNA

Z-RNA biology: a central role in the innate immune response?

Structure and Formation of Z-DNA and Z-RNA

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