Base excision repair (BER), which is initiated by DNA N-glycosylase proteins, is the frontline for repairing potentially mutagenic DNA base damage. The NTHL1 glycosylase, which excises DNA base damage caused by reactive oxygen species, is thought to be a tumor suppressor. However, in addition to NTHL1 loss-of-function mutations, our analysis of cancer genomic datasets reveals that NTHL1 frequently undergoes amplification or upregulation in some cancers. Whether NTHL1 overexpression could contribute to cancer phenotypes has not yet been explored. To address the functional consequences of NTHL1 overexpression, we employed transient overexpression. Both NTHL1 and a catalytically-dead NTHL1 (CATmut) induce DNA damage and genomic instability in non-transformed human bronchial epithelial cells (HBEC) when overexpressed. Strikingly, overexpression of either NTHL1 or CATmut causes replication stress signaling and a decrease in homologous recombination (HR). HBEC cells that overexpress NTHL1 or CATmut acquire the ability to grow in soft agar and exhibit loss of contact inhibition, suggesting that a mechanism independent of NTHL1 catalytic activity contributes to acquisition of cancer-related cellular phenotypes. We provide evidence that NTHL1 interacts with the multifunctional DNA repair protein XPG suggesting that interference with HR is a possible mechanism that contributes to acquisition of early cellular hallmarks of cancer.

中文翻译：

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碱基切除修复 NTHL1 糖基化酶的过度表达会导致基因组不稳定和癌症的早期细胞特征。

碱基切除修复 (BER) 由 DNA N-糖基化酶蛋白启动，是修复潜在诱变性 DNA 碱基损伤的前线。NTHL1 糖基化酶可以切除由活性氧引起的 DNA 碱基损伤，被认为是一种肿瘤抑制因子。然而，除了NTHL1功能丧失突变之外，我们对癌症基因组数据集的分析表明，NTHL1在某些癌症中经常发生扩增或上调。NTHL1 过度表达是否会导致癌症表型尚未得到探索。为了解决 NTHL1 过度表达的功能后果，我们采用了瞬时过度表达。当 NTHL1 和催化死亡的 NTHL1 (CATmut) 过表达时，都会在未转化的人支气管上皮细胞 (HBEC) 中诱导 DNA 损伤和基因组不稳定。引人注目的是，NTHL1 或 CATmut 的过度表达会导致复制应激信号传导和同源重组 (HR) 减少。过度表达 NTHL1 或 CATmut 的 HBEC 细胞获得在软琼脂中生长的能力并表现出接触抑制的丧失，这表明独立于 NTHL1 催化活性的机制有助于获得与癌症相关的细胞表型。我们提供的证据表明 NTHL1 与多功能 DNA 修复蛋白 XPG 相互作用，表明干扰 HR 是有助于获得癌症早期细胞标志的一种可能机制。