Merkel cell carcinoma (MCC) is an aggressive neuroendocrine cancer of the skin with high rates of metastasis and mortality. Besides well-established factors including genetic mutations and UV-induced DNA damage in Merkel cell carcinogenesis, the recent discovery of the Merkel cell polyomavirus (MCPyV) has shed light on the viral etiology of MCC. In the current study, we provide novel evidence that MCPyV small T (sT) antigen induces the DNA damage response (DDR) pathway. Our data show that in human MCC cells, the presence of MCPyV is associated with hyperphosphorylation of histone H2AX, a marker for DNA damage. We observed that overexpression of MCPyV sT antigen induced the phosphorylation of histone H2AX as well as the activation of ataxia telangiectasia mutant (ATM), an upstream kinase important for H2AX phosphorylation. Moreover, we observed that MCPyV sT expression also induced the hyperphosphorylation of other ATM downstream molecules (including 53BP1 and CHK2) as well as the hypermethylation of histone 3 and histone 4. These findings disclose a novel link between MCPyV sT and the DDR pathway in MCC. Given that measurement of DDR is clinically useful for evaluating treatment response to radio- and chemotherapy, our findings warrant further investigation to evaluate the potential implications of this pathway for MCC management.

中文翻译：

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默克尔细胞多瘤病毒Small T抗原诱导DNA损伤反应。

默克尔细胞癌（MCC）是一种侵袭性皮肤神经内分泌癌，具有很高的转移和死亡率。除了成熟的因素包括默克尔细胞癌变中的遗传突变和紫外线诱导的DNA损伤外，默克尔细胞多瘤病毒（MCPyV）的最新发现为MCC的病毒病因学提供了线索。在当前的研究中，我们提供了MCPyV小T（sT）抗原诱导DNA损伤反应（DDR）途径的新证据。我们的数据表明，在人MCC细胞中，MCPyV的存在与组蛋白H2AX（DNA损伤的标志物）的过度磷酸化有关。我们观察到，MCPyV sT抗原的过表达诱导组蛋白H2AX的磷酸化以及共济失调毛细血管扩张突变体（ATM）的激活，它是H2AX磷酸化重要的上游激酶。此外，我们观察到MCPyV sT的表达还诱导其他ATM下游分子（包括53BP1和CHK2）的超磷酸化以及组蛋白3和组蛋白4的超甲基化。鉴于DDR的测量在临床上可用于评估对放疗和化疗的治疗反应，因此我们的发现值得进一步研究，以评估该途径对MCC管理的潜在影响。