DNA folds threaten genetic stability and can be leveraged for chemotherapy

Zell, Joanna; Sperti, Francesco Rota; Britton, Sébastien; Monchaud, David

doi:10.1039/d0cb00151a

“…As G4s are intimately linked to genetic transactions (see section 2b), G4 ligands can stabilize physically barriers to polymerases in general, triggering DNA damage (Figure 4). (252,253) It may be more elegant to consider G4s as genetic switches with specific spatiotemporal control over key cellular processes, compared to considering G4s as genome-wide triggers for creating DNA damage, however this latter, simpler rationale offers a mechanistic model that accounts for most of the cell-based studies collected so far. Therefore, in light of the propensity of G4-stabilising ligands to trigger genetic instability, and the association with severe genetic dysregulations (see section 2c), it is surprising that, to date, most if not all efforts by chemical biologists have been focused on G4 stabilization rather than destabilization.…”

Section: B the Formation Of G-quadruplexes Is Intimately Linked To Genetic Transactionsmentioning

confidence: 99%

How to untie G-quadruplex knots and why?

Lejault

¹

,

Mitteaux

²

,

Sperti

³

et al. 2021

Cell Chemical Biology

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For more than two decades now, the prime objective of the chemical biology community studying G-quadruplexes (G4s) has been to use chemicals to interact with and stabilize G4s (i.e., G4-ligands) in cells to obtain mechanistic interpretations. This strategy has been undoubtedly successful, as demonstrated by the spectacular recent advances. However, these insights have also led to a fundamental rethinking of G4-targeting strategies: in light of the prevalence of G4s in the human genome, transcriptome and ncRNAome (collectively referred to as the G4ome), and particularly their involvement in human diseases (cancers and neuropathologies), should we continue to search for and develop G4-stabilizing ligands or would it not be wise to invest efforts in designing and exploiting molecular tools able to unfold G4s? Perhaps provocative, this question invites us to take a new and fresh look at the wealth of data accumulated on the functional relevance of G4s. In this review, we first focus on how, when and where G4s fold in cells; then, we describe the enzymatic systems the cells have evolved to counteract G4 folding (i.e., G4-helicases) and how they have been used as biomolecular tools to manipulate G4s in cells; finally, we present the strategies currently being implemented by chemical biologists on G4-ligands and G4-helicase to devise new molecular G4-unwinding agents.

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“…The relationship between G4 structures/motifs and the progressive discovery of proteins that modulate the dynamic of G4 formation, such as helicases or other proteins involved in DNA and RNA transactions has expanded our knowledge to understand the ubiquitous function of G4 structures on cellular metabolism and cell fate 5 , 6 , 13 , 15 , 17 – 20 , 64 . In the present study, we identified through a MS-based quantitative proteomic analysis 425 human proteins significantly enriched on constrained G4 structures relative to a duplex DNA control, in which well-described G4 interacting factors were present.…”

Section: Discussionmentioning

confidence: 99%

Constrained G4 structures unveil topology specificity of known and new G4 binding proteins

Pipier

¹

,

Devaux

²

,

Lavergne

³

et al. 2021

Sci Rep

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G-quadruplexes (G4) are non-canonical secondary structures consisting in stacked tetrads of hydrogen-bonded guanines bases. An essential feature of G4 is their intrinsic polymorphic nature, which is characterized by the equilibrium between several conformations (also called topologies) and the presence of different types of loops with variable lengths. In cells, G4 functions rely on protein or enzymatic factors that recognize and promote or resolve these structures. In order to characterize new G4-dependent mechanisms, extensive researches aimed at identifying new G4 binding proteins. Using G-rich single-stranded oligonucleotides that adopt non-controlled G4 conformations, a large number of G4-binding proteins have been identified in vitro, but their specificity towards G4 topology remained unknown. Constrained G4 structures are biomolecular objects based on the use of a rigid cyclic peptide scaffold as a template for directing the intramolecular assembly of the anchored oligonucleotides into a single and stabilized G4 topology. Here, using various constrained RNA or DNA G4 as baits in human cell extracts, we establish the topology preference of several well-known G4-interacting factors. Moreover, we identify new G4-interacting proteins such as the NELF complex involved in the RNA-Pol II pausing mechanism, and we show that it impacts the clastogenic effect of the G4-ligand pyridostatin.

show abstract

“…The relationship between G4 structures/motifs and the progressive discovery of proteins that modulate the dynamic of G4 formation, such as helicases or other proteins involved in DNA and RNA transactions has expanded our knowledge to understand the ubiquitous function of G4 structures on cellular metabolism and cell fate 5,6,13,15,[17][18][19][20]64 . In the present study, we identified through a MS-based quantitative proteomic analysis 425 human proteins significantly enriched on constrained G4 structures relative to a duplex DNA control, in which welldescribed G4 interacting factors were present.…”

Section: Discussionmentioning

confidence: 99%

Constrained G4 structures unveil topology specificity of known and new G4 binding proteins

Pipier

¹

,

Devaux

²

,

Lavergne

³

et al. 2021

Preprint

Self Cite

View full text Add to dashboard Cite

G-quadruplexes (G4) are non-canonical secondary structures consisting in stacked tetrads of hydrogen-bonded guanines bases. An essential feature of G4 is their intrinsic polymorphic nature, which is characterized by the equilibrium between several conformations (also called topologies) and the presence of different types of loops with variable lengths. In cells, G4 functions rely on protein or enzymatic factors that recognize and promote or resolve these structures. In order to characterize new G4-dependent mechanisms, extensive researches aimed at identifying new G4 binding proteins. Using G-rich single-stranded oligonucleotides that adopt non-controlled G4 conformations, a large number of G4-binding proteins have been identified in vitro, but their specificity towards G4 topology remained unknown. Constrained G4 structures are biomolecular objects based on the use of a rigid cyclic peptide scaffold as a template for directing the intramolecular assembly of the anchored oligonucleotides into a single and stabilized G4 topology. Here, using various constrained RNA or DNA G4 as baits in human cell extracts, we establish the topology preference of several well-known G4-interacting factors. Moreover, we identify new G4-interacting proteins such as the NELF complex involved in the RNA-Pol II pausing mechanism, and we show that it impacts the clastogenic effect of the G4-ligand pyridostatin.

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DNA folds threaten genetic stability and can be leveraged for chemotherapy

Abstract: Alternative DNA structures (including G-quadruplexes and DNA junctions) represent promising targets for combinatorial chemotherapeutic treatments aiming at fostering genomic instability and impeding DNA repair.

Cited by 44 publications

References 419 publications

How to untie G-quadruplex knots and why?

How to untie G-quadruplex knots and why?

Constrained G4 structures unveil topology specificity of known and new G4 binding proteins

Constrained G4 structures unveil topology specificity of known and new G4 binding proteins

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