THE ROLE OF NUCLEAR DOMAIN 10 PROTEINS IN THE HUMAN PAPILLOMAVIRUS LIFECYCLE
Stepp, Wesley Hunter
McBride, Alison A
The complete lifecycle of human papillomaviruses (HPVs) is tightly linked to the differentiation program of the human epithelium. Upon primary infection, a short burst of viral DNA replication is required to establish the viral genome as an extrachromosomal element. Once established, the viral genomes are maintained indefinitely, tethered to host chromatin, in dividing cells. As infected cells differentiate, the virus switches from maintenance replication to vegetative amplification of viral DNA. Nuclear Domain 10 (ND10) bodies are the site of viral genome delivery upon entry into the nucleus and have also been shown to localize with HPV proteins L1, L2 and E2.Here we demonstrate that Sp100, a component of the ND10 structure, represses transcription, replication and establishment of incoming viral DNA. Additionally, we independently confirm in primary human skin cells work from another group showing that the L2 protein displaces Sp100 from the ND10 body. Further, we attempted to characterize how the Sp100 protein represses viral DNA transcription and replication by overexpression and siRNA depletion of specific Sp100 isoforms. Through these studies, we have implicated the isoforms of Sp100 that contain the SAND motif as potential repressors of HPV transcription and replication.Finally, we show that ND10 bodies associate with viral replication factories upon differentiation. Once associated, Sp100 infiltrates the viral replication factories and represses viral mRNA transcription of the differentiation-dependent late genes. The involvement of PML and Sp100 at both early and late stages of the viral lifecycle highlights the importance of the two primary ND10 body proteins throughout HPV infection.
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