Oxidative lesions modulate G-quadruplex stability and structure in the human BCL2 promoter

Bielskutė, Stasė; Plavec, Janez; Podbevšek, Peter

doi:10.1093/nar/gkab057

Cited by 24 publications

(20 citation statements)

References 60 publications

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“…Dependence on location is a predominant theme that is not limited to telomeric G4s. Effects of 8oxoG were evaluated recently for the G4 antiparallel structure within the P1 promoter of Bcl2 [81]. NMR and UV melting demonstrated that 8oxoG at guanines located in an external tetrad and loop did not show significant impacts on G4 structure, whereas 8oxoG located at middle tetrad positions resulted in decreased thermostability and broader imino resonance peaks, consistent with an effect of 8oxoG on G4 structure.…”

Section: Dependence On Location and G4 Conformationmentioning

confidence: 81%

“…NMR and UV melting demonstrated that 8oxoG at guanines located in an external tetrad and loop did not show significant impacts on G4 structure, whereas 8oxoG located at middle tetrad positions resulted in decreased thermostability and broader imino resonance peaks, consistent with an effect of 8oxoG on G4 structure. This might be due to formation of an antiparallel structure with base orientations (i.e., anti or syn) and bonding partners that differ from the non-damaged sequence [81]. Though the entire G-rich sequence in the Bcl2 promoter was not evaluated, this study points to an interesting phenomenon that could translate to cells under oxidative stress.…”

Section: Dependence On Location and G4 Conformationmentioning

confidence: 91%

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Impact of G-Quadruplexes and Chronic Inflammation on Genome Instability: Additive Effects during Carcinogenesis

Stein

Eckert

2021

Genes

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Genome instability is an enabling characteristic of cancer, essential for cancer cell evolution. Hotspots of genome instability, from small-scale point mutations to large-scale structural variants, are associated with sequences that potentially form non-B DNA structures. G-quadruplex (G4) forming motifs are enriched at structural variant endpoints in cancer genomes. Chronic inflammation is a physiological state underlying cancer development, and oxidative DNA damage is commonly invoked to explain how inflammation promotes genome instability. We summarize where G4s and oxidative stress overlap, with a focus on DNA replication. Guanine has low ionization potential, making G4s vulnerable to oxidative damage. Impacts to G4 structure are dependent upon lesion type, location, and G4 conformation. Occasionally, G4s pose a challenge to replicative DNA polymerases, requiring specialized DNA polymerases to maintain genome stability. Therefore, chronic inflammation creates a dual challenge for DNA polymerases to maintain genome stability: faithful G4 synthesis and bypassing unrepaired oxidative lesions. Inflammation is also accompanied by global transcriptome changes that may impact mutagenesis. Several studies suggest a regulatory role for G4s within cancer- and inflammatory-related gene promoters. We discuss the extent to which inflammation could influence gene regulation by G4s, thereby impacting genome instability, and highlight key areas for new investigation.

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Section: Dependence On Location and G4 Conformationmentioning

confidence: 81%

Section: Dependence On Location and G4 Conformationmentioning

confidence: 91%

Impact of G-Quadruplexes and Chronic Inflammation on Genome Instability: Additive Effects during Carcinogenesis

Stein

Eckert

2021

Genes

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“…Structure of G4 and reconstruction of DARPins. The structure of the h-Telo G4 was retrieved from PDB data bank 1KF1 [43], as well as that of the c-Myc (1XAV) [44] and Bcl-2 (6ZX7) [45]. The sequences of 2E4 and 2G10 DARPins were obtained from the Supplementary Information of [35] and their structure reconstructed with the SWISS-MODEL server [46].…”

Section: Methodsmentioning

confidence: 99%

G-quadruplex recognition by DARPIns through epitope/paratope analogy

Miclot

Bignon

Terenzi³

et al. 2022

Preprint

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We investigated the mechanisms leading to the specific recognition of Guanine Guadruplex (G4) by DARPins peptides, which can lead to the design of G4s specific sensors. To this end we carried out all-atom molecular dynamic simulations to unravel the interactions between specific nucleic acids, including human-telomeric (h-telo), Bcl-2, and c-Myc, with different peptides, forming a DARPin/G4 complex. By comparing the sequences of DARPin with that of a peptide known for its high affinity for c-Myc, we show that the recognition cannot be ascribed to sequence similarity but, instead, depends on the complementarity between the three-dimensional arrangement of the molecular fragments involved: the α-helix/loops domain of DARPin and the G4 backbone. Our results reveal that DARPins tertiary structure presents a charged hollow region in which G4 can be hosted, thus the more complementary the structural shapes, the more stable the interaction.

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“…Therefore, disruption of G4 formation occurs when G is oxidized to OG. However, recent studies showed that the plasticity of G4 folding enables OG to be well accommodated and even facilitate the formation of particular G4 structures. ,, On the other hand, an OG-disrupted G4 can be recovered by adding a pyrene-conjugated G-tract …”

Section: Introductionmentioning

confidence: 99%

Oxidative Damage Induces a Vacancy G-Quadruplex That Binds Guanine Metabolites: Solution Structure of a cGMP Fill-in Vacancy G-Quadruplex in the Oxidized BLM Gene Promoter

Wang

Liu

et al. 2022

J. Am. Chem. Soc.

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Guanine (G)-oxidation to 8-oxo-7,8-dihydroguanine (OG) by reactive oxygen species in genomic DNA has been implicated with various human diseases. G-quadruplex (G4)forming sequences in gene promoters are highly susceptible to Goxidation, which can subsequently cause gene activation. However, the underlying G4 structural changes that result from OG modifications remain poorly understood. Herein, we investigate the effect of G-oxidation on the BLM gene promoter G4. For the first time, we show that OG can induce a G-vacancy-containing G4 (vG4), which can be filled in and stabilized by guanine metabolites and derivatives. We determined the NMR solution structure of the cGMP-fill-in oxidized BLM promoter vG4. This is the first complex structure of an OG-induced vG4 from a human gene promoter sequence with a filled-in guanine metabolite. The high-resolution structure elucidates the structural features of the specific 5′-end cGMP-fill-in for the OG-induced vG4. Interestingly, the OG is removed from the G-core and becomes part of the 3′-end capping structure. A series of guanine metabolites and derivatives are evaluated for fill-in activity to the oxidation-induced vG4. Significantly, cellular guanine metabolites, such as cGMP and GTP, can bind and stabilize the OG-induced vG4, suggesting their potential regulatory role in response to oxidative damage in physiological and pathological processes. Our work thus provides exciting insights into how oxidative damage and cellular metabolites may work together through a G4-based epigenetic feature for gene regulation. Furthermore, the NMR structure can guide the rational design of small-molecule inhibitors that specifically target the oxidation-induced vG4s.

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Oxidative lesions modulate G-quadruplex stability and structure in the human BCL2 promoter

Cited by 24 publications

References 60 publications

Impact of G-Quadruplexes and Chronic Inflammation on Genome Instability: Additive Effects during Carcinogenesis

Impact of G-Quadruplexes and Chronic Inflammation on Genome Instability: Additive Effects during Carcinogenesis

G-quadruplex recognition by DARPIns through epitope/paratope analogy

Oxidative Damage Induces a Vacancy G-Quadruplex That Binds Guanine Metabolites: Solution Structure of a cGMP Fill-in Vacancy G-Quadruplex in the Oxidized BLM Gene Promoter

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