Potential Roles for G-Quadruplexes in Mitochondria

Falabella, Micol; Fernández, Rafael; Johnson, F. Brad; Kaufman, Brett A.

doi:10.2174/0929867325666180228165527

Cited by 67 publications

(77 citation statements)

References 107 publications

(130 reference statements)

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“…The HSP2-derived transcript elongation defects caused by low-dose RHPS4 coincide with G4-predicted sequences residing almost exclusively in the heavy strand template. We predict that the compound binds to the displaced heavy strand, which occurs in in the major arc region between the heavy and light strand origins (OH and OL, respectively) containing twothirds of the genome during first strand replication (26). This same region acts as the template for HSP2-derived transcription, which is also affected by RHPS4.…”

Section: Discussionmentioning

confidence: 99%

“…Although the association of G4-forming sequences with mtDNA deletion breakpoints has been demonstrated (6)(7)(8), the natural function of these structures in mitochondrial biology remains elusive (26). Using a specific G4 ligand that stabilizes G4 structures in mitochondria, we have begun to understand the impact of these sequences on mitochondrial function.…”

Section: Discussionmentioning

confidence: 99%

“…In the nucleus, ligand-mediated increases in G4 stability are known to cause replication pausing (9). By extension, we expected that small molecules able to increase G4 stability in mitochondria would also cause replication pausing, leading to mtDNA depletion (26). We tested four known G4 ligands (Braco-19, NMM, Phen-DC3, and RHPS4) for their ability to induce mtDNA depletion in cultured mouse embryonic fibroblast cells ( Figure 1A).…”

Section: Identification Of Rhps4 As a Mitochondrial G4 Ligand That Inmentioning

confidence: 99%

“…Despite these connections, the role of G4 in mtDNA is unclear, requiring the development of novel reagents for their study (26). As such, we sought a means to alter mitochondrial G-quadruplex stability and assess the effect of such an alteration on mtDNA metabolism and respiratory function in normal cells.…”

Section: Introductionmentioning

confidence: 99%

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G-quadruplex dynamics contribute to epigenetic regulation of mitochondrial function

Falabella

Kolesar

Xiang

et al. 2018

Preprint

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words)Single-stranded DNA or RNA sequences rich in guanine (G) can adopt non-canonical structures known as G-quadruplexes (G4). Predicted G4-forming sequences in the mitochondrial genome are enriched on the heavy-strand and have been associated with formation of deletion breakpoints that cause mitochondrial disorders. However, the functional roles of G4 structures in regulating mitochondrial respiration in non-cancerous cells remain unclear. Here, we demonstrate that RHPS4, previously thought to be a nuclear G4-ligand, localizes primarily to mitochondria in live cells by mechanisms involving mitochondrial membrane potential. We find that RHPS4 exposure causes an acute inhibition of mitochondrial transcript elongation, leading to respiratory complex depletion. At higher ligand doses, RHPS4 causes mitochondrial DNA (mtDNA) replication pausing and genome depletion. Using these different levels of RHPS4 exposure, we describe discrete nuclear gene expression responses associated with mitochondrial transcription inhibition or with mtDNA depletion. Importantly, a mtDNA variant with increased anti-parallel G4-forming characteristic shows a stronger respiratory defect in response to RHPS4, supporting the conclusion that mitochondrial sensitivity to RHPS4 is G4-structure mediated. Thus, we demonstrate a direct role for G4 perturbation in mitochondrial genome replication, transcription processivity, and respiratory function in normal cells and describe the first molecule that differentially recognizes G4 structures in mtDNA.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Identification Of Rhps4 As a Mitochondrial G4 Ligand That Inmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

G-quadruplex dynamics contribute to epigenetic regulation of mitochondrial function

Falabella

Kolesar

Xiang

et al. 2018

Preprint

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“…Guanine-enriched sequences in other eukaryotes have been shown to adopt G-quadruplex (G4) stable structures and may play potential roles in the regulation of DNA replication, transcription and translation (Falabella et al 2019). Using G4Hunter (Brázda et al 2019),…”

Section: Evolutionary Relationships Within Bigyra and Stramenopilementioning

confidence: 99%

First genome ofLabyrinthula, an opportunistic seagrass pathogen, reveals novel insight into marine protist phylogeny, ecology and CAZyme cell-wall degradation

Tan

Loke

Croft

et al. 2020

Preprint

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Labyrinthula spp. are saprobic, marine protists that also act as opportunistic pathogens and are the causative agents of seagrass wasting disease (SWD). Despite the threat of local- and large-scale SWD outbreaks, there are currently gaps in our understanding of the drivers of SWD, particularly surrounding Labyrinthula virulence and ecology. Given these uncertainties, we investigated Labyrinthula from a novel genomic perspective by presenting the first draft genome and predicted proteome of a pathogenic isolate of Labyrinthula SR_Ha_C, generated from a hybrid assembly of Nanopore and Illumina sequences. Phylogenetic and cross-phyla comparisons revealed insights into the evolutionary history of Stramenopiles. Genome annotation showed evidence of glideosome-type machinery and an apicoplast protein typically found in protist pathogens and parasites. Proteins involved in Labyrinthula’s actin-myosin mode of transport, as well as carbohydrate degradation were also prevalent. Further, CAZyme functional predictions revealed a repertoire of enzymes involved in breakdown of cell-wall and carbohydrate storage compounds common to seagrasses. The relatively low number of CAZymes annotated from the genome of Labyrinthula SR_Ha_C compared to other Labyrinthulea species may reflect the conservative annotation parameters, a specialised substrate affinity and the scarcity of characterised protist enzymes. Inherently, there is high probability for finding both unique and novel enzymes from Labyrinthula spp. This study provides resources for further exploration of Labyrinthula ecology and evolution, and will hopefully be the catalyst for new hypothesis-driven SWD research revealing more details of molecular interactions between Labyrinthula species and its host substrate.

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Self‐Assembled Peptidyl Aggregates for the Fluorogenic Recognition of Mitochondrial DNA G‐Quadruplexes

et al. 2022

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The selective monitoring of G-quadruplex (G4) structures in living cells is important to elucidate their functions and reveal their value as diagnostic or therapeutic targets. Here we report a fluorogenic probe (CV2) able to selectively light-up parallel G4 DNA over antiparallel topologies. CV2 was constructed by conjugating the excimer-forming CV dye with a peptide sequence (L-Arg-L-Gly-glutaric acid) that specifically recognizes G4s. CV2 forms self-assembled, red excimeremitting nanoaggregates in aqueous media, but specific binding to G4s triggers its disassembly into rigidified monomeric dyes, leading to a dramatic fluorescence enhancement. Moreover, selective permeation of CV2 stains G4s in mitochondria over the nucleus. CV2 was employed for tracking the folding and unfolding of G4s in living cells, and for monitoring mitochondrial DNA (mtDNA) damage. These properties make CV2 appealing to investigate the possible roles of mtDNA G4s in diseases that involve mitochondrial dysfunction.

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Potential Roles for G-Quadruplexes in Mitochondria

Cited by 67 publications

References 107 publications

G-quadruplex dynamics contribute to epigenetic regulation of mitochondrial function

G-quadruplex dynamics contribute to epigenetic regulation of mitochondrial function

First genome ofLabyrinthula, an opportunistic seagrass pathogen, reveals novel insight into marine protist phylogeny, ecology and CAZyme cell-wall degradation

Self‐Assembled Peptidyl Aggregates for the Fluorogenic Recognition of Mitochondrial DNA G‐Quadruplexes

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