The Effect of Atypical Nucleic Acids Structures in DNA Double Strand Break Repair: A Tale of R-loops and G-Quadruplexes

Camarillo, Rosa; Jimeno, Sonia; Huertas, Pablo

doi:10.3389/fgene.2021.742434

Cited by 4 publications

(3 citation statements)

References 112 publications

(118 reference statements)

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“…Repetitive G sequences induce the formation of a planar “G-tetrad” that can stack on each other, forming a helical structure ( Figure 6 A). Notably, G quadruplexes can stabilize regulatory R-loops when formed on the displaced ssDNA (reviewed in [ 106 , 107 ]). Small molecules that bind G quadruplexes (G4 binders) have shown great promise in cancer treatment due to their cytotoxicity [ 107 , 108 ].…”

Section: Anticancer Effects Of R-loops and Their Exploitation For The...mentioning

confidence: 99%

“…Notably, G quadruplexes can stabilize regulatory R-loops when formed on the displaced ssDNA (reviewed in [ 106 , 107 ]). Small molecules that bind G quadruplexes (G4 binders) have shown great promise in cancer treatment due to their cytotoxicity [ 107 , 108 ]. Monohydrazone-based G4 binders induce cancer cell death by accumulating G4 and R-loops in the genome of cancer cells [ 109 ].…”

Section: Anticancer Effects Of R-loops and Their Exploitation For The...mentioning

confidence: 99%

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R-Loops and R-Loop-Binding Proteins in Cancer Progression and Drug Resistance

Elsakrmy

Cui

2023

IJMS

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R-loops are three-stranded DNA/RNA hybrids that form by the annealing of the mRNA transcript to its coding template while displacing the non-coding strand. While R-loop formation regulates physiological genomic and mitochondrial transcription and DNA damage response, imbalanced R-loop formation can be a threat to the genomic integrity of the cell. As such, R-loop formation is a double-edged sword in cancer progression, and perturbed R-loop homeostasis is observed across various malignancies. Here, we discuss the interplay between R-loops and tumor suppressors and oncogenes, with a focus on BRCA1/2 and ATR. R-loop imbalances contribute to cancer propagation and the development of chemotherapy drug resistance. We explore how R-loop formation can cause cancer cell death in response to chemotherapeutics and be used to circumvent drug resistance. As R-loop formation is tightly linked to mRNA transcription, their formation is unavoidable in cancer cells and can thus be explored in novel cancer therapeutics.

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Section: Anticancer Effects Of R-loops and Their Exploitation For The...mentioning

confidence: 99%

Section: Anticancer Effects Of R-loops and Their Exploitation For The...mentioning

confidence: 99%

R-Loops and R-Loop-Binding Proteins in Cancer Progression and Drug Resistance

Elsakrmy

Cui

2023

IJMS

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“…15,16,[19][20][21][22] Stabilisation of G4s using small molecules has been identi-ed as an important approach to regulate gene expression, but G4 stabilisation can increase DNA damage in cells if G4s are not efficiently regulated. 23,24 Chromatin accessibility is required for transcription, and remodelling of chromatin is central to the DNA damage response to facilitate access of repair factors for removal of the lesion. [25][26][27][28] Recently, G4 formation has been correlated with DNA damage repair and gene activation.…”

Section: Introductionmentioning

confidence: 99%

G4-DNA formation and chromatin remodelling are interdependent in human cells

Lawler

King

et al. 2023

Chem. Sci.

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Exploring the G-quadruplex binding and unwinding activity of the bacterial FeS helicase DinG

De Piante,

D’Aria,

Napolitano

et al. 2023

Sci Rep

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Despite numerous reports on the interactions of G-quadruplexes (G4s) with helicases, systematic analysis addressing the selectivity and specificity of each helicase towards a variety of G4 topologies are scarce. Among the helicases able to unwind G4s are those containing an iron-sulphur (FeS) cluster, including both the bacterial DinG (found in E. coli and several pathogenic bacteria) and the medically important eukaryotic homologues (XPD, FancJ, DDX11 and RTEL1). We carried out a detailed study of the interactions between the E. coli DinG and a variety of G4s, by employing physicochemical and biochemical methodologies. A series of G4-rich sequences from different genomic locations (promoter and telomeric regions), able to form unimolecular G4 structures with diverse topologies, were analyzed (c-KIT1, KRAS, c-MYC, BCL2, Tel23, T30695, Zic1). DinG binds to most of the investigated G4s with little discrimination, while it exhibits a clear degree of unwinding specificity towards different G4 topologies. Whereas previous reports suggested that DinG was active only on bimolecular G4s, here we show that it is also able to bind to and resolve the more physiologically relevant unimolecular G4s. In addition, when the G4 structures were stabilized by ligands (Pyridostatin, PhenDC3, BRACO-19 or Netropsin), the DinG unwinding activity decreased and in most cases was abolished, with a pattern that is not simply explained by a change in binding affinity. Overall, these results have important implications for the biochemistry of helicases, strongly suggesting that when analysing the G4 unwinding property of an enzyme, it is necessary to investigate a variety of G4 substrates.

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The Effect of Atypical Nucleic Acids Structures in DNA Double Strand Break Repair: A Tale of R-loops and G-Quadruplexes

Cited by 4 publications

References 112 publications

R-Loops and R-Loop-Binding Proteins in Cancer Progression and Drug Resistance

R-Loops and R-Loop-Binding Proteins in Cancer Progression and Drug Resistance

G4-DNA formation and chromatin remodelling are interdependent in human cells

Exploring the G-quadruplex binding and unwinding activity of the bacterial FeS helicase DinG

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