Deciphering the molecular mechanisms of SV40-induced polyploidization

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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.