Defects in 8-oxo-guanine repair pathway cause high frequency of C &gt; A substitutions in neuroblastoma

Boogaard, Marlinde L. van den; Oka, Rurika; Hakkert, Anne; Schild, Linda; Ebus, Marli E.; Gerven, Michael R. van; Zwijnenburg, Danny; Molenaar, Piet; Hoyng, Lieke; Dolman, M. Emmy M.; Essing, Anke H. W.; Koopmans, Bianca; Helleday, Thomas; Drost, Jarno; Boxtel, Ruben van; Versteeg, Rogier; Koster, Jan; Molenaar, Jan J.

doi:10.1073/pnas.2007898118

Cited by 23 publications

(17 citation statements)

References 33 publications

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“…Comparison of our 8-oxo-dG trinucleotide distribution data with SBS36 indicated a cosine similarity value of 0.85, which is among the highest observed for all available COSMIC signatures. Another type of tumor in which a ROS-mediated mutagenesis pathway seems to be at work is neuroblastoma with copy number loss of OGG1 or MUTYH as recently reported (62).…”

Section: Discussionmentioning

confidence: 96%

Concordance of hydrogen peroxide–induced 8-oxo-guanine patterns with two cancer mutation signatures of upper GI tract tumors

et al. 2022

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Oxidative DNA damage has been linked to inflammation, cancer, and aging. Here, we have mapped two types of oxidative DNA damage, oxidized guanines produced by hydrogen peroxide and oxidized thymines created by potassium permanganate, at a single-base resolution. 8-Oxo-guanine occurs strictly dependent on the G/C sequence context and shows a pronounced peak at transcription start sites (TSSs). We determined the trinucleotide sequence pattern of guanine oxidation. This pattern shows high similarity to the cancer-associated single-base substitution signatures SBS18 and SBS36. SBS36 is found in colorectal cancers that carry mutations in MUTYH , encoding a repair enzyme that operates on 8-oxo-guanine mispairs. SBS18 is common in inflammation-associated upper gastrointestinal tract tumors including esophageal and gastric adenocarcinomas. Oxidized thymines induced by permanganate occur with a distinct dinucleotide specificity, 5′T-A/C, and are depleted at the TSS. Our data suggest that two cancer mutational signatures, SBS18 and SBS36, are caused by reactive oxygen species.

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Section: Discussionmentioning

confidence: 96%

Concordance of hydrogen peroxide–induced 8-oxo-guanine patterns with two cancer mutation signatures of upper GI tract tumors

et al. 2022

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“…sgRNAs were designed using the CRISPOR design tool 40 (sgRNA sequences are listed in Table S4) and were cloned into the pSpCas9(BB)-2A-GFP (PX458) (this plasmid was a gift from Feng Zhang 41 , addgene plasmid #48138). The cloning of the sgRNAs and the two homology arm plasmids (one for ATRX_KO_sgRNA_1 and one for ATRX_KO_sgRNA_2) were performed as described by Boogaard et al 42 . The primers used for amplification of the homology arms and the PGK-eGFP-puromycin cassette are listed in Table S5.…”

Section: Methodsmentioning

confidence: 99%

“…Western blots were performed as described in Boogaard et al 42 . Primary and secondary antibodies are shown in Table S7.…”

Section: Western Blot Analysismentioning

confidence: 99%

Two opposing gene expression patterns withinATRXaberrant neuroblastoma

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Arkel

et al. 2022

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Neuroblastoma is the most common extracranial solid tumor in children. A subgroup of high-risk patients is characterized by aberrations in the chromatin remodeller ATRX that is encoded by 35 exons. In contrast to other pediatric cancer where ATRX point mutations are most frequent, multi-exon deletions (MEDs) are the most frequent type of ATRX aberrations in neuroblastoma. Of these MEDs 75% are predicted to produce in-frame fusion proteins, suggesting a potential gain-of-function effect compared to nonsense mutations. For neuroblastoma there are only a few patient-derived ATRX aberrant models. Therefore, we created isogenic ATRX aberrant models using CRISPR-Cas9 in several neuroblastoma cell lines and one tumoroid and performed total RNA-sequencing on these and on the patient-derived model. Gene set enrichment analysis (GSEA) showed decreased expression of genes related to both ribosome biogenesis and several metabolic process in our isogenic ATRX exon 2-10 MED model systems, the patient-derived MED models and in tumor data containing two patients with an ATRX exon 2-10 MED. Interestingly, for our isogenic ATRX knock-out and exon 2-13 MED models GSEA revealed an opposite expression pattern characterized by increased expression of genes related to ribosome biogenesis and several metabolic process. Our validations confirmed a potential role of ATRX in the regulation of ribosome homeostasis. In this manner we identified two distinct molecular expression patterns within ATRX aberrant neuroblastomas with important implications for the need of distinct treatment regimens.

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“…Defects in 8-oxo-dG repair are often found in patients with cancer; for example, the OGG1 locus on chromosome 3p26.2 is frequently deleted in several cancer types 57 . The 8-oxo-dG-induced G > T mutation is widespread in cancer; copy number loss of OGG1 and MUTYH in patients with neuroblastoma causes high levels of G > T substitutions with a poor survival rate 58 . Sequencing analyses of coding regions in 518 protein kinase genes have revealed that G > T is a major somatic mutation in 210 diverse human cancers 59 .…”

Section: -Oxoguanine In Dnamentioning

confidence: 99%

8-Oxoguanine: from oxidative damage to epigenetic and epitranscriptional modification

et al. 2022

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In pathophysiology, reactive oxygen species control diverse cellular phenotypes by oxidizing biomolecules. Among these, the guanine base in nucleic acids is the most vulnerable to producing 8-oxoguanine, which can pair with adenine. Because of this feature, 8-oxoguanine in DNA (8-oxo-dG) induces a G > T (C > A) mutation in cancers, which can be deleterious and thus actively repaired by DNA repair pathways. 8-Oxoguanine in RNA (o8G) causes problems in aberrant quality and translational fidelity, thereby it is subjected to the RNA decay pathway. In addition to oxidative damage, 8-oxo-dG serves as an epigenetic modification that affects transcriptional regulatory elements and other epigenetic modifications. With the ability of o8G•A in base pairing, o8G alters structural and functional RNA–RNA interactions, enabling redirection of posttranscriptional regulation. Here, we address the production, regulation, and function of 8-oxo-dG and o8G under oxidative stress. Primarily, we focus on the epigenetic and epitranscriptional roles of 8-oxoguanine, which highlights the significance of oxidative modification in redox-mediated control of gene expression.

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Defects in 8-oxo-guanine repair pathway cause high frequency of C > A substitutions in neuroblastoma

Cited by 23 publications

References 33 publications

Concordance of hydrogen peroxide–induced 8-oxo-guanine patterns with two cancer mutation signatures of upper GI tract tumors

Concordance of hydrogen peroxide–induced 8-oxo-guanine patterns with two cancer mutation signatures of upper GI tract tumors

Two opposing gene expression patterns withinATRXaberrant neuroblastoma

8-Oxoguanine: from oxidative damage to epigenetic and epitranscriptional modification

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