Background
Human papillomavirus (HPV) infection can cause benign or malignant lesions in humans. It is an envelope-less, double-stranded DNA virus containing upstream regulatory, early (E6, E7, E1, E2, E4, and E5), and late (L1, L2) regions within a genome of approximately 8 kb. In most cases, the body naturally clears the infected HPV after a period, while persistent HPV infection can lead to disease under certain factors. One of the high-risk types of HPV can lead to cervical cancer, as well as anal and other cancers of the vulva, vagina, and penis. The causative agents for nearly 15% of cervical cancers and 11% of all HPV-associated cancers are HPV31, 33, 58, 45, and 52. Prior 9-valent vaccination prevents the development of these cancers. HPV invades stratified epithelial basal cells exposed by trauma. These infected basal cells can persist until they are eliminated by the immune system or become cancerous, which is usually associated with integration of viral DNA into the host's chromosomes.
The HPV 31 genome structure is similar to other high-risk HPV types, such as HPV 16 and 18. The HPV genome consists of two major coding regions and a third regulatory region, also known as the upstream regulatory region (URR) or long control region (LCR). E6 and E7 are viral oncoproteins, whereas E1 and E2 are replication proteins. The E4 and E5 open reading frames are present in early transcripts but are synthesized at high levels only after differentiation, suggesting that they function primarily later in the viral life cycle. The E6 protein is approximately 100 amino acids in size and is localized to the cytoplasm and nuclear compartments. The E6 protein of HPV 31 interacts with a range of cytokines that contribute to cellular transformation, such as recruitment of p53 leading to its rapid turnover and activation of the catalytic subunit of telomerase leading to activation of telomerase. E7 proteins are found primarily in the nucleus and bind to members of the Rb protein family, and E7 proteins in HPV31 induce Rb degradation, leading to the structural activation of E2F family members, which leads to rapid entry into S phase. The L1 and L2 open reading frames encode coat proteins and are synthesized simultaneously during viral replication, allowing the newly replicated viral genome to be encapsulated into progeny virus particles.
Figure 1. HPV genome structure map of high-risk HPV 31
(Source: Gusho E, et al. 2021)
Alternative methods for studying HPV infection include the use of virus-like particles (VLPs) and pseudoviruses that encapsulate a reporter gene within a VLP. Creative Diagnostics is committed to providing a complete range of products and services for your HPV 31 research, including recombinant HPV 31 L1 protein (VLP) and related products.
Alternative Names
Human papillomavirus type 31 L1 protein
Human papillomavirus 31 L1 protein
HPV 31 L1
HPV 31 major capsid protein L1
References
- 1. Gusho E, et al. Human Papillomaviruses Target the DNA Damage Repair and Innate Immune Response Pathways to Allow for Persistent Infection. Viruses. 2021 Jul 17;13(7):1390.
- 2. Mobini Kesheh M, et al. Genetic diversity and bioinformatic analysis in the L1 gene of HPV genotypes 31, 33, and 58 circulating in women with normal cervical cytology. Infect Agent Cancer. 2023 Mar 23;18(1):19.
References
The SETD2 Methyltransferase Supports Productive HPV31 Replication through the LEDGF/CtIP/Rad51 Pathway
J Virol
Authors: Mac M, DeVico BM, Raspanti SM, Moody CA.
Abstract
The human papillomavirus (HPV) life cycle takes place in the stratified epithelium, with the productive phase being activated by epithelial differentiation. The HPV genome is histone-associated, and the life cycle is epigenetically regulated, in part, by histone tail modifications that facilitate the recruitment of DNA repair factors that are required for viral replication. We previously showed that the SETD2 methyltransferase facilitates the productive replication of HPV31 through the trimethylation of H3K36 on viral chromatin. SETD2 regulates numerous cellular processes, including DNA repair via homologous recombination (HR) and alternative splicing, through the recruitment of various effectors to histone H3 lysine 36 trimethylation (H3K36me3). We previously demonstrated that the HR factor Rad51 is recruited to HPV31 genomes and is required for productive replication; however, the mechanism of Rad51 recruitment has not been defined. SET domain containing 2 (SETD2) promotes the HR repair of double-strand breaks (DSBs) in actively transcribed genes through the recruitment of carboxy-terminal binding protein (CtBP)-interacting protein (CtIP) to lens epithelium-derived growth factor (LEDGF)-bound H3K36me3, which promotes DNA end resection and thereby allows for the recruitment of Rad51 to damaged sites. In this study, we found that reducing H3K36me3 through the depletion of SETD2 or the overexpression of an H3.3K36M mutant leads to an increase in γH2AX, which is a marker of damage, on viral DNA upon epithelial differentiation. This is coincident with decreased Rad51 binding. Additionally, LEDGF and CtIP are bound to HPV DNA in a SETD2-dependent and H3K36me3-dependent manner, and they are required for productive replication. Furthermore, CtIP depletion increases DNA damage on viral DNA and blocks Rad51 recruitment upon differentiation. Overall, these studies indicate that H3K36me3 enrichment on transcriptionally active viral genes promotes the rapid repair of viral DNA upon differentiation through the LEDGF-CtIP-Rad51 axis. IMPORTANCE The productive phase of the HPV life cycle is restricted to the differentiating cells of the stratified epithelium. The HPV genome is histone-associated and subject to epigenetic regulation, though the manner in which epigenetic modifications contribute to productive replication is largely undefined. In this study, we demonstrate that SETD2-mediated H3K36me3 on HPV31 chromatin promotes productive replication through the repair of damaged DNA. We show that SETD2 facilitates the recruitment of the homologous recombination repair factors CtIP and Rad51 to viral DNA through LEDGF binding to H3K36me3. CtIP is recruited to damaged viral DNA upon differentiation, and, in turn, recruits Rad51. This likely occurs through the end resection of double-strand breaks. SETD2 trimethylates H3K36me3 during transcription, and active transcription is necessary for Rad51 recruitment to viral DNA. We propose that the enrichment of SETD2-mediated H3K36me3 on transcriptionally active viral genes upon differentiation facilitates the repair of damaged viral DNA during the productive phase of the viral life cycle.
Complete genome sequence of a HPV31 isolate from laryngeal squamous cell carcinoma and biological consequences for p97 promoter activity
PLoS One
Authors: Munsamy Y, Seedat RY, Sekee TR, Bester PA, Burt FJ.
Abstract
Human papillomavirus type 31, although detected less frequently than HPV types 16 and 18, is associated with head and neck squamous cell carcinomas. Previous studies suggest that polymorphisms in the long control region (LCR) may alter the oncogenic potential of the virus. This study reports the first complete genome of a South African HPV31 isolate from a laryngeal squamous cell carcinoma. Sequence variations relative to the HPV31 prototype sequence were identified. The pBlue-Topo? vector, a reporter gene system was used to investigate the possible influence of these variations on the LCR promoter activity in vitro. Using mutagenesis to create two different fragments, β-galactosidase assays were used to monitor the effect of nucleotide variations on the p97 promoter. Increased β-galactosidase expression was observed in mutants when compared to the South African HPV31 LCR isolate. Enhanced transcriptional activity was observed with the mutant that possessed a single nucleotide change within the YY1 transcription factor binding site. In conclusion, sequence variation within the LCR of HPV31 isolates may have a functional effect on viral p97 promoter activity
COA
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