Unscheduled DNA replication origin activation at inserted HPV 18 sequences in a HPV 18/MYC amplicon
Unscheduled DNA replication origin activation at inserted HPV 18 sequences in a HPV 18/MYC amplicon
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DOI：
10.1002/gcc.20448
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发表时间：
2007-08-01
影响因子：
3.7
通讯作者：
Bensimon, Aaron
中科院分区：
文献类型：
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作者：
Conti, Chiara;Herrick, John;Bensimon, Aaron
癌基因扩增是导致肿瘤发生的关键步骤，但其潜在机制仍知之甚少。尽管数据表明 DNA 复制是基因组不稳定的主要根源，但人们对重排区域中复制起点的使用和复制叉进展知之甚少。我们使用单 DNA 分子方法，首次对宫颈癌中先前表征的 MYC/乳头瘤病毒 (HPV 18) 扩增子进行复制动力学研究。使用该扩增子作为模型，我们研究了 DNA 复制控制在人类癌症中产生扩增的作用。数据显示，与同一基因组的其他区域相比，扩增区域的 DNA 复制动力学受到严重干扰。研究发现，DNA 复制是从基因组序列和病毒序列启动的，导致起源激发的中值频率更高。此外，还发现较高的启动频率与停滞复制叉数量的相应增加相关。这些观察结果提出了一种有趣的可能性，即插入的 HPV-18 病毒 DNA 序列上的意外复制起点激活会触发该癌细胞系中的 DNA 扩增以及随后 MYC 癌基因的过度表达。
Oncogene amplification is a critical step leading to tumorigenesis, but the underlying mechanisms are still poorly understood. Despite data suggesting that DNA replication is a major source of genomic instability, little is known about replication origin usage and replication fork progression in rearranged regions. Using a single DNA molecule approach, we provide here the first study of replication kinetics on a previously characterized MYC/papillomavirus (HPV 18) amplicon in a cervical cancer. Using this amplicon as a model, we investigated the role DNA replication control plays in generating amplifications in human cancers. The data reveal severely perturbed DNA replication kinetics in the amplified region when compared with other regions of the same genome. It was found that DNA replication is initiated from both genomic and viral sequences, resulting in a higher median frequency of origin firings. In addition, it was found that the higher initiation frequency was associated with an equivalent increase in the number of stalled replication forks. These observations raise the intriguing possibility that unscheduled replication origin activation at inserted HPV-18 viral DNA sequences triggers DNA amplification in this cancer cell line and the subsequent overexpression of the MYC oncogene.