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

Nguyen, Giang Huong; Tang, Weiliang; Robles, Ana I.; Beyer, Richard P.; Gray, Lucas T.; Welsh, Judith A.; Schetter, Aaron J.; Kumamoto, Kensuke; Wang, Xin Wei; Hickson, Ian D.; Maizels, Nancy; Monnat, Raymond J.; Harris, Curtis C.

doi:10.1073/pnas.1404807111

Cited by 111 publications

(101 citation statements)

References 51 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: Discussionmentioning

confidence: 56%

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: Discussionmentioning

confidence: 56%

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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“…A recent study is done on fibroblast line cells that explain the role of redox alterations in cells, in BS phenotype. This shows the increased levels of SOD activity and overproduction of ROS in BS cells [24].…”

Section: Role Of Antioxidantsmentioning

confidence: 82%

Recq Helicase, Missense Mutations, Oxidative Stress and BLM Gene Defect in Bloom Syndrome

Sik¹,

Ali²,

Masood³

et al. 2017

IJMBOA

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

Cited by 111 publications

References 51 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

Recq Helicase, Missense Mutations, Oxidative Stress and BLM Gene Defect in Bloom Syndrome

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