One of the most abundant DNA lesions induced by oxidative stress is the highly mutagenic 8-oxoguanine (8-oxoG), which is specifically recognized by 8-oxoguanine DNA glycosylase 1 (OGG1) to initiate its repair. How DNA glycosylases find small non-helix-distorting DNA lesions amongst millions of bases packaged in the chromatin-based architecture of the genome remains an open question. Here, we used a high-throughput siRNA screening to identify factors involved in the recognition of 8-oxoG by OGG1. We show that cohesin and mediator subunits are required for re-localization of OGG1 and other base excision repair factors to chromatin upon oxidative stress. The association of OGG1 with euchromatin is necessary for the removal of 8-oxoG. Mediator subunits CDK8 and MED12 bind to chromatin and interact with OGG1 in response to oxidative stress, suggesting they participate in the recruitment of the DNA glycosylase. The oxidative stress-induced association between the cohesin and mediator complexes and OGG1 reveals an unsuspected function of those complexes in the maintenance of genomic stability.

中文翻译：

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OGG1 的染色质募集需要粘连蛋白和介体，对于有效去除 8-oxoG 至关重要。


氧化应激引起的最丰富的 DNA 损伤之一是高诱变性 8-氧鸟嘌呤 (8-oxoG)，它被 8-氧鸟嘌呤 DNA 糖基化酶 1 (OGG1) 特异性识别以启动其修复。 DNA糖基化酶如何在基于染色质的基因组结构中包装的数百万个碱基中发现小的非螺旋扭曲DNA损伤仍然是一个悬而未决的问题。在这里，我们使用高通量 siRNA 筛选来鉴定参与 OGG1 识别 8-oxoG 的因素。我们发现，在氧化应激时，OGG1 和其他碱基切除修复因子重新定位到染色质需要粘连蛋白和介导亚基。 OGG1 与常染色质的结合对于去除 8-oxoG 是必要的。介导亚基 CDK8 和 MED12 与染色质结合，并与 OGG1 相互作用以响应氧化应激，表明它们参与了 DNA 糖基化酶的募集。氧化应激诱导的粘连蛋白和介体复合物与 OGG1 之间的关联揭示了这些复合物在维持基因组稳定性方面具有意想不到的功能。