Characterization and Whole Genome Analysis of Human Papillomavirus Type 16 E1-1374∧63nt Variants

Sabol, Ivan; Matovina, Mihaela; Si-Mohamed, Ali; Grce, Magdalena

doi:10.1371/journal.pone.0041045

Cited by 12 publications

(26 citation statements)

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“…The duplication of 63 nucleotides (E1‐1374^63nt duplication] was first reported by Dong et al [], who investigated HPV16 positive cervical cancer cases in the Chinese Population. This intragenic duplication was also recently described in Croatia and Slovenia [Sabol et al, , ; Bogovac et al, ]. However, previous reports demonstrated that the E1‐1374^63nt duplication was linked with the European variant and was associated preferentially with low‐grade cervical intra‐epithelial neoplasia cases [Sabol et al, , ; Bogovac et al, ].…”

Section: Introductionsupporting

confidence: 70%

Prevalence of HPV16 E1‐1374^63nt variants in Greek women

Tsakogiannis

Kyriakopoulou

Darmis

et al. 2014

Journal of Medical Virology

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Recent studies have focused on sequence variation of the HPV16 E1 gene. The present study investigates the prevalence of E1-1374^63nt duplication in the Greek population, and the sequence variation at the 5' end of the E1 and E6 genes from samples that harbored this genetic alteration. Fifty HPV16 positive cervical samples, derived from Greek patients were investigated. The 5' end of the E1 gene was amplified through PCR and the variant amplicons were cloned, sequenced, and bioinformatically analyzed for selective pressure. The E1-1374^63nt duplication was identified in 24% of the examined samples, with the same prevalence in both high and low-grade cervical malignancies. The E1-1374^63nt duplication was linked to the European variant lineage (x² = 5.076, P < 0.024) and it was significantly associated with the nucleotide variation A1053C (x² = 23.102, P < 0.0001). Molecular evolution analyses anticipate that the E1-1374^63nt duplication induces functional constraints on the 5' end of E1 gene, and it is proposed that this duplication might not affect negatively the function or structure of the E1 protein. The E1-1374^63nt duplication is prevalent in the Greek population, whereas the A1053C variation might constitute a significant marker for the characterization of the E1-1374^63nt variant in the Greek population, thus providing significant information about viral pathogenicity.

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Section: Introductionsupporting

confidence: 70%

Prevalence of HPV16 E1‐1374^63nt variants in Greek women

Tsakogiannis

Kyriakopoulou

Darmis

et al. 2014

Journal of Medical Virology

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“…Each monomer is indicated by a different color and the center of this structure is where DNA is pulled apart by β-hairpin processes. This figure is adapted from (Sabol, Matovina, Si-Mohamed, & Grce, 2012) and https://www.intechopen.com/books/the-mechanisms-of-dnareplication/replicative-helicases-as-the-central-organizing-motor-proteins-in-themolecular-machines-of-the-elon…”

Section: E1mentioning

confidence: 99%

Human Papillomavirus Replication Regulation by Acetylation of a Conserved Lysine in the E2 Protein

Thomas

Androphy

2018

J Virol

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iii ACKNOWLEDGEMENTS I would like to thank my supervisor Elliot J. Androphy for his guidance, and encouragement over these many years. I truly appreciate your faith and continuous support.I also want to thank all members of the Androphy lab, for your guidance, critiques, and support.Thank you to my thesis committee, without whom none of this would be possible.Your guidance has been invaluable. Michael Klemsz, Suk-Hee Lee, Lindsey Mayo, and Andy Yu. The Papillomavirus E2 protein is a sequence specific DNA binding protein that recruits cellular factors to its genome in infected epithelial cells. E2 also binds to and loads the viral E1 DNA helicase at the origin of replication. Post-translational modifications of PV E2 have been identified as potential regulators of E2 functions. We recently reported lysine (K) 111 as a target of p300 acetylation in B(bovine)PV that is involved in the regulation of viral transcription. K111 is conserved in most papillomaviruses, so we pursued a mutational approach to query the functional significance of lysine in HPV E2. Amino acid substitutions that prevent acetylation, including arginine, were unable to stimulate transcription and E1 mediated DNA replication. The arginine K111 mutant retained E2 transcriptional repression, nuclear localization, DNA and chromatin binding, and association with E2 binding partners involved in PV transcription and replication. v When directly investigating origin unwinding, the replication defective E2 K111R mutant recruited E1 to the viral replication origin, but surprisingly, unwinding of the duplex DNA did not occur. In contrast, the glutamine K111 mutant increased origin melting and stimulated replication compared to wild type E2. We have identified Topoisomerase I as a key host factor involved in viral replication whose recruitment is dependent on K111 acetylation, and propose a new model for viral origin dynamics during replication initiation. This work reveals a novel activity of E2 necessary for denaturing the viral origin that likely depends on acetylation of highly conserved lysine 111. Human Papillomaviruses and DiseaseThere are over 200 HPVs that have been described and they manifest in a variety of ways; they can be asymptomatic, or they can result in benign lesions (papillomas) or progress to malignancy (de Villiers, Fauquet, Broker, Bernard, & zur Hausen, 2004). In the United States, HPV is the most common sexually transmitted infection and nearly all sexually active adults contract it at least once. E1The PV E1 protein is an essential viral replication factor (Lusky & Botchan, 1985;Ustav, Ustav, Szymanski, & Stenlund, 1991). E1 is the viral helicase and initiates replication by binding to specific sequences on the viral genome with the assistance of the E2 protein (Frattini & Laimins, 1994).There is sequence and functional homology between PV E1 and SV (simian virus) 40 Large T Antigen which allowed for many of the predictions concerning E2 shows differential affinity for the E2BS and it is proposed that at low levels, E2b...

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“…Most oncogenic or high-risk (HR) types associated with invasive cervical cancer (Li et al, 2011; Munoz et al, 2003; Smith et al, 2007) are clustered in one clade of the alpha-HPVs that contains species groups alpha-5, alpha-6, alpha-7 and alpha-9 (Burk et al, 2009; Schiffman et al, 2005) and account for ∼90% of all cervical cancers worldwide (Li et al, 2011; Smith et al, 2007). Despite phylogenetic relatedness, HPV variants can differ in pathogenicity (Berumen et al, 2001; Burk et al, 2003; Chan et al, 2013; Cornet et al, 2013b; Giannoudis and Herrington, 2001; Hecht et al, 1995; Sabol et al, 2012; Schiffman et al, 2010; Villa et al, 2000; Xi et al, 2007). Because of their medical importance, the predominant research focus on papillomaviruses is their association with pathologic and oncogenic lesions.…”

Section: Introductionmentioning

confidence: 99%

“…Comparison between all sequences identified a total of 540 single nucleotide polymorphisms (SNPs) with any pair of sequences having a maximum of 180 (2.3% of genome) differences. In addition to these genomes, Sabol et al (2012) have reported a 63 bp duplication within the E1 ORF (HPV16 (E1).1374_1436dup, also listed as E1-1374^63nt duplication) and 76 complete HPV16 genomes were sequenced from central China (Sun et al, 2012), although the heterogeneity was limited to the A lineages. The most striking observation about HPV16 variants is the presence of genetic heterogeneity in what is called the “non-European” lineages (i.e., lineages B/C/D) in contrast to the relative homogeneity of the A (European) lineage.…”

Section: Introductionmentioning

confidence: 99%

Human papillomavirus genome variants

2013

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Amongst the human papillomaviruses (HPVs), the genus Alphapapillomavirus contains HPV types that are uniquely pathogenic. They can be classified into species and types based on genetic distances between viral genomes. Current circulating infectious HPVs constitute a set of viral genomes that have evolved with the rapid expansion of the human population. Viral variants were initially identified through restriction enzyme polymorphisms and more recently through sequence determination of viral fragments. Using partial sequence information, the history of variants, and the association of HPV variants with disease will be discussed with the main focus on the recent utilization of full genome sequence information for variant analyses. The use of multiple sequence alignments of complete viral genomes and phylogenetic analyses have begun to define variant lineages and sublineages using empirically defined differences of 1.0–10.0% and 0.5–1.0%, respectively. These studies provide the basis to define the genetics of HPV pathogenesis.

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Characterization and Whole Genome Analysis of Human Papillomavirus Type 16 E1-1374∧63nt Variants

Cited by 12 publications

References 64 publications

Prevalence of HPV16 E1‐1374^63nt variants in Greek women

Prevalence of HPV16 E1‐1374^63nt variants in Greek women

Human Papillomavirus Replication Regulation by Acetylation of a Conserved Lysine in the E2 Protein

Human papillomavirus genome variants

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