Targeting OGG1 arrests cancer cell proliferation by inducing replication stress

Visnes, Torkild; Benítez‐Buelga, Carlos; Cázares‐Körner, Armando; Sanjiv, Kumar; Hanna, Bishoy; Mortusewicz, Oliver; Rajagopal, Varshni; Albers, Julian J; Hagey, Daniel W.; Bekkhus, Tove; Eshtad, Saeed; Baquero, Juan Miguel; Masuyer, Geoffrey; Wallner, Olov; Müller, Sarah; Pham, T. M.; Göktürk, Camilla; Rasti, Azita; Suman, Sharda; Torres-Ruíz, Raúl; Sarno, Antonio; Wiita, Elisée; Homan, Evert; Karsten, Stella; Marimuthu, Karthick; Michel, Maurice; Koolmeister, Tobias; Scobie, Martin; Loseva, Olga; Almlöf, Ingrid; Unterlass, J.E.; Pettke, Aleksandra; Boström, Johan; Pandey, Monica; Gad, Helge; Herr, Patrick; Andaloussi, Samir El; Kalderén, Christina; Rodríguez-Perales, Sandra; Benı́tez, Javier; Krokan, Hans E.; Altun, Mikael; Stenmark, Pål; Helleday, Thomas

doi:10.1093/nar/gkaa1048

Cited by 38 publications

(39 citation statements)

References 67 publications

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“…TH5487 is a selective OGG1 inhibitor that binds OGG1’s active site, causing accumulation of genomic 8-oxoG lesions as detected by mass spectrometry [ 13 ]. Consistently, immunostaining of 8-oxoG lesions and a modified comet assay have both demonstrated that TH5487 treatment indeed results in an increase in 8-oxoG level in DNA [ 42 , 43 ]. We show that TH5487 does not engage with recombinant NEIL1 ( Figure 1 ) excluding an off-target interaction between TH5487 and NEIL1.…”

Section: Discussionmentioning

confidence: 82%

“…Inhibition of OGG1 by TH5487 results in accumulation of genomic 8-oxoG lesions [ 13 , 42 , 43 ]. Similarly, we show here that siRNA-mediated OGG1 depletion also leads to accumulation of 8-oxoG lesions in DNA after menadione treatment ( Figure 6 b).…”

Section: Discussionmentioning

confidence: 99%

“…Previously, we reported the development of TH5487, a potent selective OGG1 inhib itor that binds OGG1′s active site, hampering its binding to DNA and causing accumula tion of genomic 8-oxoG lesions in cells [13,42,43]. Since 8-oxoG is prone to further oxida tion into spiroiminodihydantoin (Sp) and guanidinohydantoin (Gh) [14][15][16], we aimed to study if NEIL1 can function as a backup glycosylase after enzymatic inhibition of OGG1 Differential scanning fluorimetry (DSF) showed that TH5487 does not bind to NEIL1 (Fig ure 1), excluding off-target interaction of TH5487 with NEIL1.…”

Section: Ogg1 Inhibitor Th5487 Does Not Bind To Neil1mentioning

confidence: 99%

“…Whether backup mechanisms are activated once a specific glycosylase is inhibited has remained elusive due to the absence of specific small molecule glycosylase inhibitors. We previously reported the development of TH5487, an active site OGG1 inhibitor [ 13 , 42 , 43 ]. Here, we sought to analyze if NEIL1 or NEIL2 can function as backup BER enzymes for OGG1.…”

Section: Introductionmentioning

confidence: 99%

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NEIL1 and NEIL2 Are Recruited as Potential Backup for OGG1 upon OGG1 Depletion or Inhibition by TH5487

Hanna

Michel

Helleday

et al. 2021

IJMS

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DNA damage caused by reactive oxygen species may result in genetic mutations or cell death. Base excision repair (BER) is the major pathway that repairs DNA oxidative damage in order to maintain genomic integrity. In mammals, eleven DNA glycosylases have been reported to initiate BER, where each recognizes a few related DNA substrate lesions with some degree of overlapping specificity. 7,8-dihydro-8-oxoguanine (8-oxoG), one of the most abundant DNA oxidative lesions, is recognized and excised mainly by 8-oxoguanine DNA glycosylase 1 (OGG1). Further oxidation of 8-oxoG generates hydantoin lesions, which are recognized by NEIL glycosylases. Here, we demonstrate that NEIL1, and to a lesser extent NEIL2, can potentially function as backup BER enzymes for OGG1 upon pharmacological inhibition or depletion of OGG1. NEIL1 recruitment kinetics and chromatin binding after DNA damage induction increase in cells treated with OGG1 inhibitor TH5487 in a dose-dependent manner, whereas NEIL2 accumulation at DNA damage sites is prolonged following OGG1 inhibition. Furthermore, depletion of OGG1 results in increased retention of NEIL1 and NEIL2 at damaged chromatin. Importantly, oxidatively stressed NEIL1- or NEIL2-depleted cells show excessive genomic 8-oxoG lesions accumulation upon OGG1 inhibition, suggesting a prospective compensatory role for NEIL1 and NEIL2. Our study thus exemplifies possible backup mechanisms within the base excision repair pathway.

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Section: Discussionmentioning

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Section: Ogg1 Inhibitor Th5487 Does Not Bind To Neil1mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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NEIL1 and NEIL2 Are Recruited as Potential Backup for OGG1 upon OGG1 Depletion or Inhibition by TH5487

Hanna

Michel

Helleday

et al. 2021

IJMS

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“…Therefore, in case of deficient or overwhelmed repair in response to an important level of oxidative damage, the level of replicative stress and subsequent DSB are increased leading to cell death. Thus, it has been recently proposed than BER proteins, such as OGG1, could be potential targets for cancer treatment [71].…”

Section: Oxidative Lesions: "Natural" Causes Of Replicative Stressmentioning

confidence: 99%

A Link between Replicative Stress, Lamin Proteins, and Inflammation

Willaume

Rass

Fontanilla-Ramirez

et al. 2021

Genes

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Double-stranded breaks (DSB), the most toxic DNA lesions, are either a consequence of cellular metabolism, programmed as in during V(D)J recombination, or induced by anti-tumoral therapies or accidental genotoxic exposure. One origin of DSB sources is replicative stress, a major source of genome instability, especially when the integrity of the replication forks is not properly guaranteed. To complete stalled replication, restarting the fork requires complex molecular mechanisms, such as protection, remodeling, and processing. Recently, a link has been made between DNA damage accumulation and inflammation. Indeed, defects in DNA repair or in replication can lead to the release of DNA fragments in the cytosol. The recognition of this self-DNA by DNA sensors leads to the production of inflammatory factors. This beneficial response activating an innate immune response and destruction of cells bearing DNA damage may be considered as a novel part of DNA damage response. However, upon accumulation of DNA damage, a chronic inflammatory cellular microenvironment may lead to inflammatory pathologies, aging, and progression of tumor cells. Progress in understanding the molecular mechanisms of DNA damage repair, replication stress, and cytosolic DNA production would allow to propose new therapeutical strategies against cancer or inflammatory diseases associated with aging. In this review, we describe the mechanisms involved in DSB repair, the replicative stress management, and its consequences. We also focus on new emerging links between key components of the nuclear envelope, the lamins, and DNA repair, management of replicative stress, and inflammation.

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Optimization of N‐Piperidinyl‐Benzimidazolone Derivatives as Potent and Selective Inhibitors of 8‐Oxo‐Guanine DNA Glycosylase 1

et al. 2022

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8‐oxo Guanine DNA Glycosylase 1 is the initiating enzyme within base excision repair and removes oxidized guanines from damaged DNA. Since unrepaired 8‐oxoG could lead to G : C→T : A transversion, base removal is of utmost importance for cells to ensure genomic integrity. For cells with elevated levels of reactive oxygen species this dependency is further increased. In the past we and others have validated OGG1 as a target for inhibitors to treat cancer and inflammation. Here, we present the optimization campaign that led to the broadly used tool compound TH5487. Based on results from a small molecule screening campaign, we performed hit to lead expansion and arrived at potent and selective substituted N‐piperidinyl‐benzimidazolones. Using X‐ray crystallography data, we describe the surprising binding mode of the most potent member of the class, TH8535. Here, the N‐Piperidinyl‐linker adopts a chair instead of a boat conformation which was found for weaker analogues. We further demonstrate cellular target engagement and efficacy of TH8535 against a number of cancer cell lines.

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Targeting OGG1 arrests cancer cell proliferation by inducing replication stress

Cited by 38 publications

References 67 publications

NEIL1 and NEIL2 Are Recruited as Potential Backup for OGG1 upon OGG1 Depletion or Inhibition by TH5487

NEIL1 and NEIL2 Are Recruited as Potential Backup for OGG1 upon OGG1 Depletion or Inhibition by TH5487

A Link between Replicative Stress, Lamin Proteins, and Inflammation

Optimization of N‐Piperidinyl‐Benzimidazolone Derivatives as Potent and Selective Inhibitors of 8‐Oxo‐Guanine DNA Glycosylase 1

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