8-oxo-7,8-dihydroguanine (OG) is one of the most abundant oxidative lesions in the genome and is associated with genome instability. Its mutagenic potential is counteracted by a concerted action of 8-oxoguanine DNA glycosylase (OGG1) and mutY homolog DNA glycosylase (MUTYH). It has been suggested that OG and its repair has epigenetic-like properties and mediates transcription, but genome-wide evidence of this interdependence is lacking. Here, we applied an improved OG-sequencing approach reducing artificial background oxidation and RNA-sequencing to correlate genome-wide distribution of OG with gene transcription in OGG1 and/or MUTYH-deficient cells. Our data identified moderate enrichment of OG in the genome that is mainly dependent on the genomic context and not affected by DNA glycosylase-initiated repair. Interestingly, no association was found between genomic OG deposition and gene expression changes upon loss of OGG1 and MUTYH. Regardless of DNA glycosylase activity, OG in promoter regions correlated with expression of genes related to metabolic processes and damage response pathways indicating that OG functions as a cellular stress sensor to regulate transcription. Our work provides novel insights into the mechanism underlying transcriptional regulation by OG and DNA glycosylases OGG1 and MUTYH and suggests that oxidative DNA damage accumulation and its repair utilize different pathways.

中文翻译：

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基因组 8-氧代鸟嘌呤调节基因转录，独立于 DNA 糖基化酶 OGG1 和 MUTYH 的修复


8-氧代-7,8-二氢鸟嘌呤 （OG） 是基因组中最丰富的氧化损伤之一，与基因组不稳定性有关。其诱变潜力被 8-氧鸟嘌呤 DNA 糖基化酶 （OGG1） 和 mutY 同源 DNA 糖基化酶 （MUTYH） 的协同作用所抵消。有人认为 OG 及其修复具有表观遗传样特性并介导转录，但缺乏这种相互依赖性的全基因组证据。在这里，我们应用了一种改进的 OG 测序方法，减少了人工背景氧化和 RNA 测序，以将 OG 的全基因组分布与 OGG1 和/或 MUTYH 缺陷细胞中的基因转录相关联。我们的数据确定了基因组中 OG 的适度富集，这主要取决于基因组环境，不受 DNA 糖基化酶启动的修复的影响。有趣的是，在 OGG1 和 MUTYH 丢失后，基因组 OG 沉积与基因表达变化之间没有发现关联。无论 DNA 糖基化酶活性如何，启动子区域中的 OG 与代谢过程和损伤反应通路相关基因的表达相关，表明 OG 作为细胞应激传感器起调节转录的作用。我们的工作为 OG 和 DNA 糖基化酶 OGG1 和 MUTYH 的转录调控机制提供了新的见解，并表明氧化 DNA 损伤积累及其修复利用不同的途径。