Dynamic roles for G4 DNA in the biology of eukaryotic cells

Maizels, Nancy

doi:10.1038/nsmb1171

Cited by 393 publications

(374 citation statements)

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“…G-quadruplexes are found within DNAs in eukaryotic telomeres (66); the promoter regions of some cancer-related genes, including BCL2 (67), KIT (68), MYB (69), MYC (70), HIF1A (71), hTERT (72), KRAS (73), RB (74), and VEGF (75); immunoglobulin gene switch regions (76); and ribosomal genes (77). G4-intercalating agents have been assessed for anticancer ther-apy (57,50,51).…”

Section: Discussionmentioning

confidence: 99%

An RNA-binding Protein, Lin28, Recognizes and Remodels G-quartets in the MicroRNAs (miRNAs) and mRNAs It Regulates

O’Day

Imai

et al. 2015

Journal of Biological Chemistry

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Background: Lin28 is an evolutionary conserved RNA-binding protein that regulates miRNAs and mRNAs; Lin28 overexpression is linked to poor prognosis in cancer. Results: Lin28 binds to guanine-rich miRNAs and mRNAs that contain G-quartet structural features and remodels these structures. Conclusion: Lin28 recognition of G-quartets is a unifying feature of Lin28-regulated RNAs. Significance: Small molecules that bind to G-quartets might be useful inhibitors of Lin28 function.

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Section: Discussionmentioning

confidence: 99%

An RNA-binding Protein, Lin28, Recognizes and Remodels G-quartets in the MicroRNAs (miRNAs) and mRNAs It Regulates

O’Day

Imai

et al. 2015

Journal of Biological Chemistry

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“…Similar phenomena could also occur in eukaryotic cells; for example, extended R loops were recently shown to cause replication blockage in mammalian cells (41). Since hPu/hPy repeats (42) and G-rich stretches (43) are abundant in eukaryotic genomes, the proposed mechanism of transcription-dependent replication blockage could contribute to gross chromosomal rearrangements at these sequences in various genetic processes.…”

Section: Mechanism Of Transcription Blockage By G N ∕C N Sequences Anmentioning

confidence: 99%

Mechanisms and implications of transcription blockage by guanine-rich DNA sequences

Belotserkovskii

Liu

Tornaletti

et al. 2010

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

135

143

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Various DNA sequences that interfere with transcription due to their unusual structural properties have been implicated in the regulation of gene expression and with genomic instability. An important example is sequences containing G-rich homopurinehomopyrimidine stretches, for which unusual transcriptional behavior is implicated in regulation of immunogenesis and in other processes such as genomic translocations and telomere function. To elucidate the mechanism of the effect of these sequences on transcription we have studied T7 RNA polymerase transcription of G-rich sequences in vitro. We have shown that these sequences produce significant transcription blockage in an orientation-, lengthand supercoiling-dependent manner. Based upon the effects of various sequence modifications, solution conditions, and ribonucleotide substitutions, we conclude that transcription blockage is due to formation of unusually stable RNA/DNA hybrids, which could be further exacerbated by triplex formation. These structures are likely responsible for transcription-dependent replication blockage by G-rich sequences in vivo.R-loops | DNA supercoiling | Hoogsteen base pairing | inosine | 7-deazaquanosine S equence-specific modulation of transcription, including transcription blockage or impediment, plays an important role in DNA transactions, for example, transcription-related mutagenesis and recombination (reviewed in refs. 1 and 2) and could also be responsible for several severe genetic diseases (reviewed in refs. 3-5).Among the DNA sequences that could affect transcription are GC-rich homopurine-homopyrimidine (hPu/hPy) stretches. These sequences could form unusual DNA structures, including triplexes and G quadruplexes (reviewed in refs. 3-5), which have been implicated in several transcription-dependent phenomena (for example, see refs. 6-9).Another important property of these sequences is a dramatic asymmetry in the stabilities of RNA/DNA duplexes: The rPu/dPy duplex is significantly more stable, whereas the rPy/dPu duplex is less stable than a DNA/DNA duplex of the same sequence (10). The increased stability of rPu/dPy duplexes is likely responsible for stable R-loop formation by these sequences (11), although alternative DNA structures might also be involved (8,12,13).The simplest example of GC-rich hPu/hPy sequences, the G n ∕C n repeats, is abundant in various genomes, including transcribed domains (14, 15).The G 32 ∕C 32 stretch was previously shown to stall DNA replication in Escherichia coli plasmids in vivo (16). Remarkably, this effect was observed only when the sequence was transcribed, which led to a model stipulating that this sequence stalled an elongating RNA polymerase, and the stalled transcription complex, in turn, blocked the replication machinery (16).To elucidate the mechanism of transcription blockage by this sequence, we have studied its effect on T7 RNA polymerase (T7 RNAP) transcription in vitro, using various sequence modifications and solution conditions that allowed us to discriminate between possible D...

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“…[23][24][25][26] Since then, many groups have speculated about potential relationships between telomeric G-quadruplex structures and chromosomal end capping activities. [34,35] Interestingly, nearly all reported telomeric sequences can fold into Gquadruplex structures in vitro. [20][21][22][23][24][25][26] While it may be an incredible coincidence that diverse telomeric sequences can fold into a family of closely related structures, there is growing evidence that G-quadruplex DNA plays a direct role in telomere structure and stability in certain organisms.…”

Section: Evidence For Telomeric G-quadruplex Dnamentioning

confidence: 99%

“…G-quadruplex DNA structures are highly attractive targets given the abundance of detailed information available regarding their structures, [20,21] thermodynamic stabilities, [22] and potential biological activities -some of which might be considered cancer-specific. [21,31,[33][34][35]46] A growing number of groups are targeting G-quadruplex DNA with small molecules hoping to inhibit cancer growth according to two distinct mechanisms (Fig. 4).…”

Section: G-quadruplex Dna As a Potential Drug Targetmentioning

confidence: 99%

“…Intermolecular G-quadruplex structures have been proposed as intermediates or precursors of recombination and/or viral integration, [23,31,32] while intramolecular Gquadruplexes have been implicated in the regulation of gene expression and chromosome stability. [33][34][35] No consensus sequence for G-quadruplex folding has been experimentally determined, but approximately 370'000 sequences with the putative G-quadruplex-forming motif (G 3+ N 1-7 ) 4+ (where G = guanosine and N = any base) are dispersed throughout the human genome. [36,37] These sequences are concentrated in promoter regions, [14,38,39] introns, [36] 5' and 3' UTRs, [40] and at the ends of eukaryotic chromosomes.…”

Section: Introductionmentioning

confidence: 99%

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Targeting G-Quadruplex DNA with Small Molecules

Luedtke¹

2009

Chimia

100

105

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Despite a recent explosion of interest in G-quadruplex DNA, most fundamental questions regarding the possible presence and function of these intriguing structures in vivo remain unanswered. Cell-permeable G-quadruplex specific probes should provide researchers with new tools for studying these alternately folded DNA structures and their potential involvement in gene expression, chromosome stability, viral integration, and recombination. In this review, a survey of the binding affinity, specificity, and biological/pharmacological activities of some well-characterized G-quadruplex ligands is presented along with the potential importance of G-quadruplex DNA in vivo.134 CHIMIA 2009, 63, No. 3 Young AcAdemics in switzerlAnd PArt ii doi:10.2533doi:10. /chimia.2009doi:10. .134 Chimia 63 (2009 Despite a recent explosion of interest in G-quadruplex DNA, most fundamental questions regarding the possible presence and function of these intriguing structures in vivo remain unanswered. Cell-permeable Gquadruplex specific probes should provide researchers with new tools for studying these alternately folded DNA structures and their potential involvement in gene expression, chromosome stability, viral integration, and recombination. In this review, a survey of the binding affinity, specificity, and biological/pharmacological activities of some well-characterized G-quadruplex ligands is presented along with the potential importance of G-quadruplex DNA in vivo.

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Dynamic roles for G4 DNA in the biology of eukaryotic cells

Cited by 393 publications

References 50 publications

An RNA-binding Protein, Lin28, Recognizes and Remodels G-quartets in the MicroRNAs (miRNAs) and mRNAs It Regulates

An RNA-binding Protein, Lin28, Recognizes and Remodels G-quartets in the MicroRNAs (miRNAs) and mRNAs It Regulates

Mechanisms and implications of transcription blockage by guanine-rich DNA sequences

Targeting G-Quadruplex DNA with Small Molecules

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