Genetic interactions of G-quadruplexes in humans

Zyner, Katherine G.; Mulhearn, Darcie S; Adhikari, Santosh; Cuesta, Sergio Martínez; Antonio, Marco Di; Erard, Nicolas; Hannon, Gregory J.; Tannahill, David; Balasubramanian, Shankar

doi:10.7554/elife.46793

Cited by 98 publications

(93 citation statements)

References 133 publications

(122 reference statements)

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“…Additional experiments with this IgH switch region-containing recombination reporter system showed that Top1-catalyzed removal of transcription-associated negative supercoils is essential to avert the G4 DNA-induced recombination ensuing upon G4 DNA folding. The importance of Top1 function in preventing the detrimental effect of G4 DNA was confirmed in human cells where Top1 was shown to protect cells from the genotoxic effect of the G4-binding small molecules [35].…”

Section: The Role Of Top1 In Preventing the Formation Of G4 Dna And Omentioning

confidence: 90%

“…Of note, additional mutations not listed that are located in the core domain of Top1 can also result in reduced enzyme catalysis, like the G365S mutation found in a CPT-resistant colorectal cancer cell line as described above [96]. Top1 is required to suppress recombination and instability at a highly transcribed G4-motif in yeast and suppresses the genotoxic effect of G4-ligands in human cells [33][34][35]. siRNA-mediated knock-down of Top1 in mouse cells elevates CSR and chromosomal translocations involving the G4 DNA-forming IgH switch region sequences [31,32].…”

Section: Top1 Mutants In Cancer Cells and G4-induced Genomic Instabilitymentioning

confidence: 99%

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The Functional Consequences of Eukaryotic Topoisomerase 1 Interaction with G-Quadruplex DNA

Berroyer

Kim

2020

Genes

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Topoisomerase I in eukaryotic cells is an important regulator of DNA topology. Its catalytic function is to remove positive or negative superhelical tension by binding to duplex DNA, creating a reversible single-strand break, and finally religating the broken strand. Proper maintenance of DNA topological homeostasis, in turn, is critically important in the regulation of replication, transcription, DNA repair, and other processes of DNA metabolism. One of the cellular processes regulated by the DNA topology and thus by Topoisomerase I is the formation of non-canonical DNA structures. Non-canonical or non-B DNA structures, including the four-stranded G-quadruplex or G4 DNA, are potentially pathological in that they interfere with replication or transcription, forming hotspots of genome instability. In this review, we first describe the role of Topoisomerase I in reducing the formation of non-canonical nucleic acid structures in the genome. We further discuss the interesting recent discovery that Top1 and Top1 mutants bind to G4 DNA structures in vivo and in vitro and speculate on the possible consequences of these interactions.

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Section: The Role Of Top1 In Preventing the Formation Of G4 Dna And Omentioning

confidence: 90%

Section: Top1 Mutants In Cancer Cells and G4-induced Genomic Instabilitymentioning

confidence: 99%

The Functional Consequences of Eukaryotic Topoisomerase 1 Interaction with G-Quadruplex DNA

Berroyer

Kim

2020

Genes

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“…The importance of these sequences in numerous physiological processes is now becoming increasingly clear. Studies on the role of G4s can now rely on the development of novel G4 ligands that allow their detection in different cellular processes in vivo [83]. At present, the function of G-quadruplex DNA has been already defined in different regulatory pathways and they appear to play a role in the control of transcription and even the firing of origin of replication.…”

Section: Int J Mol Sci 2020 21 X For Peer Review 11 Of 28mentioning

confidence: 99%

From R-Loops to G-Quadruplexes: Emerging New Threats for the Replication Fork

Maffia

Ranise

Sabbioneda

2020

IJMS

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Replicating the entire genome is one of the most complex tasks for all organisms. Research carried out in the last few years has provided us with a clearer picture on how cells preserve genomic information from the numerous insults that may endanger its stability. Different DNA repair pathways, coping with exogenous or endogenous threat, have been dissected at the molecular level. More recently, there has been an increasing interest towards intrinsic obstacles to genome replication, paving the way to a novel view on genomic stability. Indeed, in some cases, the movement of the replication fork can be hindered by the presence of stable DNA: RNA hybrids (R-loops), the folding of G-rich sequences into G-quadruplex structures (G4s) or repetitive elements present at Common Fragile Sites (CFS). Although differing in their nature and in the way they affect the replication fork, all of these obstacles are a source of replication stress. Replication stress is one of the main hallmarks of cancer and its prevention is becoming increasingly important as a target for future chemotherapeutics. Here we will try to summarize how these three obstacles are generated and how the cells handle replication stress upon their encounter. Finally, we will consider their role in cancer and their exploitation in current chemotherapeutic approaches.

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“…In general, G-rich sequences may adopt into various G-quadruplex (G4) structures, which depend on their sequences and lengths, loop composition, and flanking nucleotides in K + solution [4][5][6][7][8][9][10][11][12]. Accumulating evidence on the biological functions of G4 structures in regulating multiple cellular processes [13][14][15][16][17][18] and imaging-based studies on G4 antibodies and G4 ligands for visualizing the presence of G4s in cells [19][20][21][22][23] support the existence of G4 structure in vivo. Given that structural properties of G4s are critical for biomedical implication and drug development, many questions on structural variation as a result of sequence deviation are yet to be addressed.…”

Section: Introductionmentioning

confidence: 99%

Effects of Length and Loop Composition on Structural Diversity and Similarity of (G3TG3NmG3TG3) G-Quadruplexes

Chu

Yeh

et al. 2020

Molecules

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A G-rich sequence containing three loops to connect four G-tracts with each ≥2 guanines can possibly form G-quadruplex structures. Given that all G-quadruplex structures comprise the stacking of G-quartets, the loop sequence plays a major role on their folding topology and thermal stability. Here circular dichroism, NMR, and PAGE are used to study the effect of loop length and base composition in the middle loop, and a single base difference in loop 1 and 3 on G-quadruplex formation of (G3HG3NmG3HG3) sequences with and without flanking nucleotides, where H is T, A, or C and N is T, A, C, or G. In addition, melting curve for G-quadruplex unfolding was used to provide relatively thermal stability of G-quadruplex structure after the addition of K+ overnight. We further studied the effects of K+ concentration on their stability and found structural changes in several sequences. Such (G3HG3NmG3HG3) configuration can be found in a number of native DNA sequences. The study of structural diversity and similarity from these sequences may allow us to establish the correlation between model sequences and native sequences. Moreover, several sequences upon interaction with a G-quadruplex ligand, BMVC, show similar spectral change, implying that structural similarity is crucial for drug development.

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Genetic interactions of G-quadruplexes in humans

Cited by 98 publications

References 133 publications

The Functional Consequences of Eukaryotic Topoisomerase 1 Interaction with G-Quadruplex DNA

The Functional Consequences of Eukaryotic Topoisomerase 1 Interaction with G-Quadruplex DNA

From R-Loops to G-Quadruplexes: Emerging New Threats for the Replication Fork

Effects of Length and Loop Composition on Structural Diversity and Similarity of (G3TG3NmG3TG3) G-Quadruplexes

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