Indiana University-Purdue University Indianapolis (IUPUI) / Human papillomaviruses (HPVs) are non-enveloped, circular double-stranded
DNA viruses that infect basal keratinocytes of stratified squamous epithelia.
High-risk HPV (HR-HPV) infection causes nearly all cervical cancers and an
increasing number of head and neck cancers. While prophylactic vaccinations
have reduced the incidence of HPV infection and attributable cancers, currently
there is no cure for pre-existing HPV infection. As such, HPV remains a global
health threat and a better understanding of HPV biology remains of significant
medical importance for identification of novel therapeutic targets.
The multi-subunit structural maintenance of chromosomes 5/6 complex (SMC5/6)
is comprised of SMC5, SMC6 and NSE1-4. SMC5/6 is essential for homologous
recombination DNA repair and reportedly functions as an antiviral factor during
hepatitis B and herpes simplex-1 viral infections. Intriguingly, SMC5/6 has been
found to associate with HR-HPV E2 proteins, which are multifunctional
transcription factors essential to regulation of viral replication and transcription.
The function of SMC5/6 associations with E2, as well as its role during HR-HPV
infection remain unclear and we explored this question in the context of HR-HPV-
31. SMC6 interacted with HPV-31 E2 and co-immunoprecipitation of SMC6/E2
complexes required the E2 transactivation domain, inferring SMC6 association is
limited to the full-length E2 isoform. Depletion of SMC6 and NSE3 increased
HPV replication and transcription in keratinocytes stably maintaining episomal
HPV-31, suggesting that the SMC5/6 complex represses these processes.
Neither SMC6 nor NSE3 co-IP the viral E1 DNA helicase alone or E1/E2
complexes but the association of SMC6 with E2 was reduced in the presence of
E1, indicating that SMC6 competes with E1 for E2 binding. This infers that SMC6
repression of the viral replicative program may involve inhibiting initiation of viral
replication by disrupting E2 interactions with E1. Chromatin immunoprecipitation
determined that SMC6 is present on episomal HPV-31 genomes, alluding to a
possible role for SMC5/6 in modifying the chromatin state of viral DNA. Taken
together, these findings describe a novel function for SMC5/6 as a repressor of
the HPV-31 replicative program.
| Identifer | oai:union.ndltd.org:IUPUI/oai:scholarworks.iupui.edu:1805/24609 |
| Date | 10 1900 |
| Creators | Gibson, Ryan Taylor |
| Contributors | Androphy, Elliot, Guo, Haitao, Yu, Andy, Mayo, Lindsey |
| Source Sets | Indiana University-Purdue University Indianapolis |
| Language | en_US |
| Detected Language | English |
| Type | Dissertation |
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