Genomic damage and cancer cell death caused by reactive oxygen species

8-氧代鸟嘌呤（8-oxoG）是DNA或核苷酸中的主要氧化碱基损伤之一，并且由于其可以与腺嘌呤以及胞嘧啶配对而具有高度致突变性。为了使哺乳动物基因组中8-oxoG的积累最小化，MTH 1将8-oxo-dGTP水解为8-oxo-dGMP，OGG 1切除DNA中与胞嘧啶配对的8-oxoG，而MUTYH切除DNA复制过程中插入模板DNA中与8-oxoG相对的腺嘌呤，已知其缺陷会导致MUTYH相关的家族性腺瘤性息肉病。我们发现8-oxoG在细胞核或线粒体DNA中的积累启动了MUTYH依赖的细胞死亡，并揭示了其调控机制，从而证明了细胞死亡对肿瘤抑制至关重要。

8-Oxoguanine (8-oxoG) is one of the major oxidative base lesions in DNA or nucleotides, and is highly mutagenic because it can pair with adenine as well as cytosine. To minimize accumulation of 8-oxoG in mammalian genomes, MTH1 hydrolyzes 8-oxo-dGTP to 8-oxo-dGMP, and OGG1 excises 8-oxoG paired with cytosine in DNA, while MUTYH excises adenine inserted opposite 8-oxoG in template DNA during DNA replication and whose deficiency is known to cause MUTYH-associated familial adenomatous polyposis. We found that the buildup of 8-oxoG in nuclear or mitochondrial DNA initiates MUTYH-dependent cell death, and unveiled its regulatory mechanisms, thus demonstrating that the cell death is crucial for tumor suppression.