The Role of the Smc5/6 Complex in the Papillomavirus Replication Cycle

Abstract

Papillomaviruses cause proliferative epithelial lesions and the high-risk subtypes are the causative agent of cervical cancer. These small DNA viruses largely rely on interactions with host cell machinery to complete their replication cycle. The papillomavirus E2 protein is the major replicative protein of papillomaviruses. It influences transcription of viral genes and is required for viral DNA replication and persistence of the viral genome in infected cells. Because E2 lacks enzymatic activity, many of its functions are mediated by interactions with host cell machinery. Proteomic experiments have identified an interaction of the host Smc5/6 complex with the E2 proteins of various papillomavirus types. The Smc5/6 complex is a member of the cohesin and condensin, structural maintenance of chromosomes family of proteins and is conserved in all eukaryotes. It is activated by the DNA damage response and is essential for DNA double-strand break repair through homologous recombination. Here, I investigated the role of Smc5/6 in various E2 functions. The papillomavirus replication cycle is tightly linked to the differentiation state of the host cell, where viral DNA undergoes three modes of DNA replication. My studies confirm the interaction with E2 and suggest that Smc5/6 may play different roles in the different types of viral DNA replication. Experiments utilizing a cell line derived from a cervical intraepithelial neoplasia, harboring episomal copies of high-risk HPV31b DNA, indicate that the Smc5/6 complex is required for maintenance of viral episomes in host cells. This suggests a possible mechanism by which E2 ensures long-term persistence of HPV.