The E1 proteins

Bergvall, Monika; Melendy, Thomas; Archambault, Jacques

doi:10.1016/j.virol.2013.07.020

Cited by 199 publications

(198 citation statements)

References 170 publications

(345 reference statements)

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“…DNA replication is initiated by E2 binding both to specific sequences within the viral origin of replication and to E1, the DNA helicase motor protein that drives the progression of the HPV DNA replication fork (9)(10)(11). At the origin, E2 assists E1 to assemble into a doublehexameric complex that unwinds the dsDNA ahead of the DNA replication forks (9)(10)(11). The E1 helicase also recruits and coordinates the actions of several cellular DNA replication factors required for HPV DNA synthesis, including topoisomerase I, the single-stranded-DNA (ssDNA)-binding complex (RPA), and the polymerase ␣-primase complex (7,9,10).…”

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confidence: 99%

“…At the origin, E2 assists E1 to assemble into a doublehexameric complex that unwinds the dsDNA ahead of the DNA replication forks (9)(10)(11). The E1 helicase also recruits and coordinates the actions of several cellular DNA replication factors required for HPV DNA synthesis, including topoisomerase I, the single-stranded-DNA (ssDNA)-binding complex (RPA), and the polymerase ␣-primase complex (7,9,10).…”

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confidence: 99%

“…The many biochemical studies on the enzymatic functions of various E1 proteins and the availability of high-resolution crystal structures and functional assays to probe E1's DNA replication activity both in vitro and in vivo have made E1 one of the best paradigms for the study of hexameric replicative DNA helicases (9,10).…”

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“…1A) (10). At the core of the E1 HD lies the nucleoside triphosphate (NTP)-binding site characteristic of superfamily 3 DNA helicases (amino acids [aa] 407 to 557 for bovine papillomavirus 1 [BPV1] E1 and aa 452 to 603 for HPV11 E1; PROSITE domain profile PS51206 [13,14]), flanked on the N-terminal side by the oligomerization domain (Oligo) (15) and on the other side by a C-terminal domain (CTD) comprised of an alpha helix followed by an approximately 45-amino-acid-long region that is predicted to be unstructured and that has been called either the "flexible brace" (FB) (16) or the "C-terminal module" (CTM) (17), depending on the study.…”

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Requirement for the E1 Helicase C-Terminal Domain in Papillomavirus DNA Replication In Vivo

Bergvall

Gagnon

Titolo

et al. 2016

J Virol

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The papillomavirus (PV) E1 helicase contains a conserved C-terminal domain (CTD), located next to its ATP-binding site, whose function in vivo is still poorly understood. The CTD is comprised of an alpha helix followed by an acidic region (AR) and a C-terminal extension termed the C-tail. Recent biochemical studies on bovine papillomavirus 1 (BPV1) E1 showed that the AR and C-tail regulate the oligomerization of the protein into a double hexamer at the origin. In this study, we assessed the importance of the CTD of human papillomavirus 11 (HPV11) E1 in vivo, using a cell-based DNA replication assay. Our results indicate that combined deletion of the AR and C-tail drastically reduces DNA replication, by 85%, and that further truncation into the alpha-helical region compromises the structural integrity of the E1 helicase domain and its interaction with E2. Surprisingly, removal of the C-tail alone or mutation of highly conserved residues within the domain still allows significant levels of DNA replication (55%). This is in contrast to the absolute requirement for the C-tail reported for BPV1 E1 in vitro and confirmed here in vivo. Characterization of chimeric proteins in which the AR and C-tail from HPV11 E1 were replaced by those of BPV1 indicated that while the function of the AR is transferable, that of the C-tail is not. Collectively, these findings define the contribution of the three CTD subdomains to the DNA replication activity of E1 in vivo and suggest that the function of the C-tail has evolved in a PV type-specific manner. IMPORTANCEWhile much is known about hexameric DNA helicases from superfamily 3, the papillomavirus E1 helicase contains a unique C-terminal domain (CTD) adjacent to its ATP-binding site. We show here that this CTD is important for the DNA replication activity of HPV11 E1 in vivo and that it can be divided into three functional subdomains that roughly correspond to the three conserved regions of the CTD: an alpha helix, needed for the structural integrity of the helicase domain, followed by an acidic region (AR) and a C-terminal tail (C-tail) that have been shown to regulate the oligomerization of BPV1 E1 in vitro. Characterization of E1 chimeras revealed that, while the function of the AR could be transferred from BPV1 E1 to HPV11 E1, that of the C-tail could not. These results suggest that the E1 CTD performs multiple functions in DNA replication, some of them in a virus type-specific manner.H uman papillomaviruses (HPVs) are small viruses with double-stranded DNA (dsDNA) genomes that infect both outer and mucosal stratified epithelium (for a recent review see reference 1). Of the more than 180 HPV genotypes described to date, about 20% infect the anogenital tract, causing either benign or precancerous lesions (2). In addition to their well-established role in inducing cervical and other anogenital cancers, HPVs have more recently been shown to be the causative agents for the majority of oropharyngeal cancers (3, 4).Only two HPV proteins, E1 and E2, are required for replicati...

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confidence: 99%

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confidence: 99%

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confidence: 99%

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confidence: 99%

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Requirement for the E1 Helicase C-Terminal Domain in Papillomavirus DNA Replication In Vivo

Bergvall

Gagnon

Titolo

et al. 2016

J Virol

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BRD4 as a potential target for human papillomaviruses associated cancer

Rani,

Bonam,

Zhou

et al. 2023

Journal of Medical Virology

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Around 99% of cervical cancer and 5%–10% of human cancer are associated with human papillomaviruses (HPV). Notably, the life‐cycle of HPV begins by low‐level infection of the basal cells of the stratified epithelium, where the viral genomes are replicated and passed on to the daughter proliferating basal cells. The production of new viral particles remains restricted to eventually differentiated cells. HPVs support their persistent infectious cycle by hijacking pivotal pathways and cellular processes. Bromodomain‐containing protein 4 (BRD4) is one of the essential cellular factors involved in multiple stages of viral transcription and replication. In this review, we demonstrate the role of BRD4 in the multiple stages of HPV infectious cycle. Also, we provide an overview of the intense research about the cellular functions of BRD4, the mechanism of action of bromodomain and extra terminal inhibitors, and how it could lead to the development of antiviral/anticancer therapies.

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RNA elements that control human papillomavirus mRNA splicing‐targets for therapy?

Schwartz,

Wu,

Kajitani

2024

Journal of Medical Virology

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Human papillomaviruses (HPVs) cause more than 4.5% of all cancer in the world and more than half of these cases are attributed to human papillomavirus type 16 (HPV16). Prophylactic vaccines are available but antiviral drugs are not. Novel targets for therapy are urgently needed. Alternative RNA splicing is extensively used by HPVs to express all their genes and HPV16 is no exception. This process must function to perfection since mis‐splicing could perturb the HPV gene expression program by altering mRNA levels or by generating dysfunctional mRNAs. Cis‐acting RNA elements on the viral mRNAs and their cognate cellular trans‐acting factors control papillomavirus RNA splicing. The precise but delicate nature of the splicing process renders splicing sensitive to interference. As such, papillomavirus RNA splicing is a potential target for therapy. Here we summarize our current understanding of cis‐acting HPV16 RNA elements that control HPV16 mRNA splicing via cellular proteins and discuss how they may be exploited as targets for therapy to papillomavirus infections and cancer.

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The E1 proteins

Cited by 199 publications

References 170 publications

Requirement for the E1 Helicase C-Terminal Domain in Papillomavirus DNA Replication In Vivo

Requirement for the E1 Helicase C-Terminal Domain in Papillomavirus DNA Replication In Vivo

BRD4 as a potential target for human papillomaviruses associated cancer

RNA elements that control human papillomavirus mRNA splicing‐targets for therapy?

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