G quadruplexes are genomewide targets of transcriptional helicases XPB and XPD

Gray, Lucas T.; Vallur, Aarthy C.; Eddy, Johanna; Maizels, Nancy

doi:10.1038/nchembio.1475

Cited by 193 publications

(194 citation statements)

References 60 publications

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“…The fact that many cells can readily take up G4DNA indicates that this mechanism may also allow the cell to respond to its external environment as well as internal stress (67,72). Although our results suggest important roles for G4DNA in the regulation of cytoplasmic cellular processes, other studies have suggested roles for G4DNA in modulating transcription through the binding of helicases such as DHX36 (30,96,97), the RecQ family helicases (98,99), and the XPB and XPD helicases (75). It is possible that any G4DNA-binding protein may be regulated by freely diffusing G4DNA, leading to various cellular responses based on the large number of proteins that are reported to have G4DNA binding capacity (4, 100 -102).…”

Section: Discussioncontrasting

confidence: 47%

“…2I) were also found in stress granules induced by G4DNA. The fraction of stress granule protein foci that contain G4DNA foci was determined to be 90,7,75,96,17, and 83% of the TIA1, DHX36, YB-1, ELAV1, G3BP, and eIF3 foci, respectively. The fraction of DHX36 and G3BP foci containing G4DNA was significantly lower than the other stress granule proteins.…”

Section: Resultsmentioning

confidence: 99%

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Evidence That G-quadruplex DNA Accumulates in the Cytoplasm and Participates in Stress Granule Assembly in Response to Oxidative Stress

Byrd¹,

Zybailov

Maddukuri³

et al. 2016

Journal of Biological Chemistry

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Cells engage numerous signaling pathways in response to oxidative stress that together repair macromolecular damage or direct the cell toward apoptosis. As a result of DNA damage, mitochondrial DNA or nuclear DNA has been shown to enter the cytoplasm where it binds to "DNA sensors," which in turn initiate signaling cascades. Here we report data that support a novel signaling pathway in response to oxidative stress mediated by specific guanine-rich sequences that can fold into G-quadruplex DNA (G4DNA). In response to oxidative stress, we demonstrate that sequences capable of forming G4DNA appear at increasing levels in the cytoplasm and participate in assembly of stress granules. Identified proteins that bind to endogenous G4DNA in the cytoplasm are known to modulate mRNA translation and participate in stress granule formation. Consistent with these findings, stress granule formation is known to regulate mRNA translation during oxidative stress. We propose a signaling pathway whereby cells can rapidly respond to DNA damage caused by oxidative stress. Guanine-rich sequences that are excised from damaged genomic DNA are proposed to enter the cytoplasm where they can regulate translation through stress granule formation. This newly proposed role for G4DNA provides an additional molecular explanation for why such sequences are prevalent in the human genome.

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Section: Discussioncontrasting

confidence: 47%

Section: Resultsmentioning

confidence: 99%

Evidence That G-quadruplex DNA Accumulates in the Cytoplasm and Participates in Stress Granule Assembly in Response to Oxidative Stress

Byrd¹,

Zybailov

Maddukuri³

et al. 2016

Journal of Biological Chemistry

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“…These facts suggest G-quadruplex structures have implications in physiological processes. Indeed, experimental investigations have demonstrated the physiological function of G-quadruplexes in many aspects (5)(6)(7)(8).…”

mentioning

confidence: 99%

Guanine-vacancy–bearing G-quadruplexes responsive to guanine derivatives

Zheng

Zhang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

104

144

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G-quadruplex structures formed by guanine-rich nucleic acids are implicated in essential physiological and pathological processes and nanodevices. G-quadruplexes are normally composed of four Gn (n ≥ 3) tracts assembled into a core of multiple stacked G-quartet layers. By dimethyl sulfate footprinting, circular dichroism spectroscopy, thermal melting, and photo-cross-linking, here we describe a unique type of intramolecular G-quadruplex that forms with one G 2 and three G 3 tracts and bears a guanine vacancy (G-vacancy) in one of the G-quartet layers. The G-vacancy can be filled up by a guanine base from GTP or GMP to complete an intact G-quartet by Hoogsteen hydrogen bonding, resulting in significant G-quadruplex stabilization that can effectively alter DNA replication in vitro at physiological concentration of GTP and Mg 2+ . A bioinformatic survey shows motifs of such G-quadruplexes are evolutionally selected in genes with unique distribution pattern in both eukaryotic and prokaryotic organisms, implying such G-vacancy-bearing G-quadruplexes are present and play a role in gene regulation. Because guanine derivatives are natural metabolites in cells, the formation of such G-quadruplexes and guanine fill-in (G-fill-in) may grant an environment-responsive regulation in cellular processes. Our findings thus not only expand the sequence definition of G-quadruplex formation, but more importantly, reveal a structural and functional property not seen in the standard canonical G-quadruplexes.G -quadruplexes are four-stranded structures formed in guanine-rich nucleic acids (1-3). Canonical G-quadruplexes are composed of four tracts of consecutive guanines connected by three loops. The guanines in the guanine tracts (G tracts) are packed in a core unit (Fig. 1A) of a stack of multiple G-quartet layers, each with four guanine bases connected by eight Hoogsteen hydrogen bonds (Fig. 1B). G-quadruplex-forming sequences are not randomly distributed in the mammalian genomes but concentrated at physiologically relevant positions (4): for instance, promoters, telomeres, and immuno-globulin switch regions. These facts suggest G-quadruplex structures have implications in physiological processes. Indeed, experimental investigations have demonstrated the physiological function of G-quadruplexes in many aspects (5-8).Studies on G-quadruplexes have mostly focused on sequences described by a consensus of G ≥3 (N 1-7 G ≥3 ) ≥3 , which can potentially form G-quadruplexes of three or more G-quartet layers with three loops of one to seven nucleotides (Fig. 1A) (9, 10). In recent years, the definition describing the capability of G-quadruplex formation has been broadened. Sequences with a loop up to 11 or 15 nucleotides were found capable of forming stable G-quadruplexes when the other two loops are sufficiently short (11, 12). The continuity of guanines in G tracts was also relaxed by the finding of G-quadruplexes with broken (13, 14) or bulged (15, 16) G tracts. Besides these intramolecular G-quadruplexes in single-stranded DNA (ssDNA), ...

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“…G4 DNA can be bound and unwound by RECQ helicases (10), and by the XPD-related helicases such as human XPD (19) and its paralogs FANCJ (20,21), CHL1 (22), and likely RTEL1 (23). In the human genome, G4 motifs are greatly enriched near transcription start sites (TSS), at the 5′ end of first introns, and in exons and introns of many oncogenes (reviewed in refs.…”

mentioning

confidence: 99%

Regulation of gene expression by the BLM helicase correlates with the presence of G-quadruplex DNA motifs

Nguyen

Tang²,

Robles

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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111

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Significance Bloom syndrome is a rare human genetic disease characterized by proportional dwarfism, immunodeficiency, and an elevated risk of many different cancer types. We used RNA expression profiling to identify networks of mRNAs and microRNAs that are differentially expressed in cells from Bloom syndrome patients and associated with cell proliferation, survival, and molecular pathways promoting cancer. Altered mRNA expression was in some cases strongly correlated with the presence of G4 motifs, which may form G-quadruplex targets that are bound by BLM. Further analysis of the genetic networks we identified may elucidate mechanisms responsible for Bloom syndrome disease pathogenesis and ways to ameliorate or prevent disease in affected individuals.

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G quadruplexes are genomewide targets of transcriptional helicases XPB and XPD

Cited by 193 publications

References 60 publications

Evidence That G-quadruplex DNA Accumulates in the Cytoplasm and Participates in Stress Granule Assembly in Response to Oxidative Stress

Evidence That G-quadruplex DNA Accumulates in the Cytoplasm and Participates in Stress Granule Assembly in Response to Oxidative Stress

Guanine-vacancy–bearing G-quadruplexes responsive to guanine derivatives

Regulation of gene expression by the BLM helicase correlates with the presence of G-quadruplex DNA motifs

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