Genomic damage and cancer cell death caused by reactive oxygen species

8-氧鸟嘌呤（8-oxoG）是DNA或核苷酸中主要的氧化碱基损伤之一，由于它可以与腺嘌呤和胞嘧啶配对，因此具有高度的诱变性。为了减少8-oxoG在哺乳动物基因组中的积累，MTH1将8-oxo-dGTP水解为8-oxo-dGMP， OGG1切除DNA中与胞嘧啶配对的8-oxoG，而MUTYH在DNA复制过程中切除模板DNA中插入与8-oxoG相反的腺嘌呤，其缺陷已知会导致MUTYH相关的家族性腺瘤性息肉病。我们发现细胞核或线粒体DNA中8-oxoG的积累启动了mutyh依赖性细胞死亡，并揭示了其调控机制，从而证明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.