Deciphering the molecular mechanisms of SV40-induced polyploidization

在感染期间，病毒试图控制细胞，而宿主则通过包括DNA损伤反应途径在内的各种防御系统进行反应。获得控制是通过首先利用细胞DNA损伤反应途径的特定成分，然后使其失活来实现的。超越正常检查点控制的目的是迫使宿主细胞然后维持在S期，以确保充足的核苷酸和其他必要的复制因子的供应。这种控制的一个例子来自猿猴病毒40(SV40)，在这种病毒感染下，依赖ATM的DNA损伤反应被激活，随后信号级联的某些关键蛋白失活，如P53和MRN亚单位NBS1。此外，研究还表明，SV40介导的Nbs1失活可触发细胞DNA和含有SV40原基的应答蛋白的内复制。然而，我们的研究表明，宿主的P53状态在SV40诱导的内复制中也起着重要作用。数据表明，SV40依赖于转录活性Ap53，Ap53是p21上调所必需的活性，从而抑制细胞周期蛋白A-CDK2。在SV40感染的细胞中，细胞周期蛋白A-CDK2活性的失活是维持细胞处于S期并破坏复制起始控制的先决条件。然而，SV40诱导多倍化的信号通路及其组成以及分子机制仍有待阐明。

During infection, viruses attempt to take hold of the cell while the host responds with various defense systems including the DNA damage response pathway. Gaining control is accomplished by first exploiting and then inactivating specific components of the cellular DNA damage response pathway. The purpose of overriding normal checkpoint control is to force and then maintain the host cell in S-phase to ensure an abundant supply of nucleotides and other essential replication factors. An example of this type of control comes from Simian Virus 40 (SV40), In which viral infection leads to activation ofan ATM-dependent DNA damage response, followed by inactivation of certain key proteins ofthe signaling cascade such as p53 and the MRN-subunit Nbs1. In addition, it was shown that SV40-mediated inactivation of Nbs1 triggers endoreplication of cellular DNA and SV40 origin-containing repllcons. However, our Investigations revealed that the p53 status of the host also plays an important part in SV40-induced endoreplication. Data demonstrate that SV40 depends on transcriptional active Ap53, an activity that is essential for p21 upregulation and hence cyclin A-Cdk2 inhibition. In SV40 infected cells inactivation of cyclin A-Cdk2 activity Is a prerequisite for maintaining cells in S-phase and disrupting replication initiation control. However, the signaling pathways and their components as well as the molecular mechanisms that underlie SV40-induced polyploidization remain to be elucidated.