Effect of DNA Glycosylases OGG1 and Neil1 on Oxidized G-Rich Motif in the KRAS Promoter

Ferino, Annalisa; Xodo, Luigi E.

doi:10.3390/ijms22031137

Cited by 4 publications

(3 citation statements)

References 53 publications

(93 reference statements)

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“…The VEGF promoter PQS is susceptible to oxidative damage in both its B‐form and G4 conformations (Fleming et al, 2015) and it remains unclear at what stage of the 8oxoG induced, BER‐dependent gene enhancement mechanism the DNA adopts the required G4 fold. Prior studies utilizing single‐stranded DNA G4 substrates have consistently revealed a lack of and/or very weak OGG1 glycosylase activity toward G4 DNA containing 8oxoG (Ferino and Xodo, 2021; Zhou et al, 2015). Moreover, OGG1 has been shown not to have activity on non‐G4 single‐stranded DNA substrates as well (Franck et al, 2022).…”

Section: Discussionmentioning

confidence: 99%

“…Prior studies utilizing single-stranded DNA G4 substrates have consistently revealed a lack of and/or very weak OGG1 glycosylase activity toward G4 DNA containing 8oxoG (Ferino and Xodo, 2021;Zhou et al, 2015). Moreover, OGG1 has been shown not to have activity on non-G4 single-stranded DNA substrates as well (Franck et al, 2022).…”

Section: Ligation Depends On Fen1mentioning

confidence: 99%

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Oxidative DNA damage on the VEGF G‐quadruplex forming promoter is repaired via long‐patch BER

Hussen,

Kravitz,

Freudenthal

et al. 2023

Environ and Mol Mutagen

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In response to oxidative damage, base excision repair (BER) enzymes perturb the structural equilibrium of the VEGF promoter between B‐form and G4 DNA conformations, resulting in epigenetic‐like modifications of gene expression. However, the mechanistic details remain enigmatic, including the activity and coordination of BER enzymes on the damaged G4 promoter. To address this, we investigated the ability of each BER factor to conduct its repair activity on VEGF promoter G4 DNA substrates by employing pre‐steady‐state kinetics assays and in vitro coupled BER assays. OGG1 was able to initiate BER on double‐stranded VEGF promoter G4 DNA substrates. Moreover, pre‐steady‐state kinetics revealed that compared to B‐form DNA, APE1 repair activity on the G4 was decreased ~two‐fold and is the result of slower product release as opposed to inefficient strand cleavage. Interestingly, Pol β performs multiple insertions on G4 substrates via strand displacement DNA synthesis in contrast to a single insertion on B‐form DNA. The multiple insertions inhibit ligation of the Pol β products, and hence BER is not completed on the VEGF G4 promoter substrates through canonical short‐patch BER. Instead, repair requires the long‐patch BER flap‐endonuclease activity of FEN1 in response to the multiple insertions by Pol β prior to ligation. Because the BER proteins and their repair activities are a key part of the VEGF transcriptional enhancement in response to oxidative DNA damage of the G4 VEGF promoter, the new insights reported here on BER activity in the context of this promoter are relevant toward understanding the mechanism of transcriptional regulation.

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Section: Discussionmentioning

confidence: 99%

Section: Ligation Depends On Fen1mentioning

confidence: 99%

Oxidative DNA damage on the VEGF G‐quadruplex forming promoter is repaired via long‐patch BER

Hussen,

Kravitz,

Freudenthal

et al. 2023

Environ and Mol Mutagen

View full text Add to dashboard Cite

show abstract

“…G4 folding also influences processing of DNA lesions by BER enzymes, and can thereby influence gene expression when the lesion resides in a G-rich promoter (for review see (Fleming and Burrows, 2020). While NEIL1 and NEIL3 glycosylases can remove hydantoin lesions from a G4, OGG1 is unable to recognize and excise 8-oxoG residing in a telomeric or promoter G4 (Zhou et al, 2013;Zhou et al, 2015;Ferino and Xodo, 2021). Whether MUTYH can excise A in the context of a G4 is unknown but is unlikely given that the A:8-oxoG base pair is disrupted in a G4.…”

Section: -Oxog Formation and Repair In The Context Of Telomeric G-quadruplex Structures: Beneficial Or Detrimental For Telomere Stabilitymentioning

confidence: 99%

Roles for the 8-Oxoguanine DNA Repair System in Protecting Telomeres From Oxidative Stress

Rosa

Johnson

Opresko

2021

Front. Cell Dev. Biol.

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Telomeres are protective nucleoprotein structures that cap linear chromosome ends and safeguard genome stability. Progressive telomere shortening at each somatic cell division eventually leads to critically short and dysfunctional telomeres, which can contribute to either cellular senescence and aging, or tumorigenesis. Human reproductive cells, some stem cells, and most cancer cells, express the enzyme telomerase to restore telomeric DNA. Numerous studies have shown that oxidative stress caused by excess reactive oxygen species is associated with accelerated telomere shortening and dysfunction. Telomeric repeat sequences are remarkably susceptible to oxidative damage and are preferred sites for the production of the mutagenic base lesion 8-oxoguanine, which can alter telomere length homeostasis and integrity. Therefore, knowledge of the repair pathways involved in the processing of 8-oxoguanine at telomeres is important for advancing understanding of the pathogenesis of degenerative diseases and cancer associated with telomere instability. The highly conserved guanine oxidation (GO) system involves three specialized enzymes that initiate distinct pathways to specifically mitigate the adverse effects of 8-oxoguanine. Here we introduce the GO system and review the studies focused on investigating how telomeric 8-oxoguanine processing affects telomere integrity and overall genome stability. We also discuss newly developed technologies that target oxidative damage selectively to telomeres to investigate roles for the GO system in telomere stability.

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G-quadruplex DNA: a novel target for drug design

Teng

Jiang

Guo

et al. 2021

Cell. Mol. Life Sci.

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Effect of DNA Glycosylases OGG1 and Neil1 on Oxidized G-Rich Motif in the KRAS Promoter

Cited by 4 publications

References 53 publications

Oxidative DNA damage on the VEGF G‐quadruplex forming promoter is repaired via long‐patch BER

Oxidative DNA damage on the VEGF G‐quadruplex forming promoter is repaired via long‐patch BER

Roles for the 8-Oxoguanine DNA Repair System in Protecting Telomeres From Oxidative Stress

G-quadruplex DNA: a novel target for drug design

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