Initial amplification of the HPV18 genome proceeds via two distinct replication mechanisms

Orav, Marit; Geimanen, Jelizaveta; Sepp, Eva-Maria; Henno, Liisi; Ustav, Ene; Ustav, Mart

doi:10.1038/srep15952

Cited by 24 publications

(58 citation statements)

References 62 publications

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“…It has become clear in recent years that HPVs activate the DNA damage response network during their replication to “invite” cellular replication and DNA repair proteins to their replication foci[ 50 ]. Moreover, it has been shown that HPV uses homologous recombination to efficiently replicate its genome[ 39 , 40 ]. The exact mechanism and all the necessary cellular partners are not yet known.…”

Section: Discussionmentioning

confidence: 99%

“…U2OS cells, which are derived from moderately differentiated osteosarcoma, have an adherent epithelial morphology and carry wild-type p53 and pRB genes, which have proven to be useful for studying various aspects of the HPV life cycle[ 36 – 38 ]. It has been shown that the replication mechanism of HPVs in U2OS cells is identical to other cell lines, such as HaCat cells[ 39 , 40 ]. In addition to describing replication, transcriptome analyses of mucosal HPVs 11 and 18 and cutaneous HPV 5 have been published[ 41 – 43 ].…”

Section: Introductionmentioning

confidence: 99%

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Identification of several high-risk HPV inhibitors and drug targets with a novel high-throughput screening assay

et al. 2017

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Human papillomaviruses (HPVs) are oncogenic viruses that cause numerous different cancers as well as benign lesions in the epithelia. To date, there is no effective cure for an ongoing HPV infection. Here, we describe the generation process of a platform for the development of anti-HPV drugs. This system consists of engineered full-length HPV genomes that express reporter genes for evaluation of the viral copy number in all three HPV replication stages. We demonstrate the usefulness of this system by conducting high-throughput screens to identify novel high-risk HPV-specific inhibitors. At least five of the inhibitors block the function of Tdp1 and PARP1, which have been identified as essential cellular proteins for HPV replication and promising candidates for the development of antivirals against HPV and possibly against HPV-related cancers.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Identification of several high-risk HPV inhibitors and drug targets with a novel high-throughput screening assay

et al. 2017

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“…The viral E1 and E2 proteins are not present in the virion, so viral transcription with accompanying synthesis of these proteins is assumed to occur very early after infection. A recent study found that replication begins at the viral ori and proceeds through a theta structure model, although subsequent replication appeared to be unidirectional and did not initiate at a specific site [ 59 ]. Viral copy number is maintained in proliferating basal keratinocytes and in vitro cultured cells that carry PV episomes, which presumably requires viral origin licensing during G1/S after which the replicated genomes partition without triggering the mitotic spindle dependent checkpoint [ 60 ].…”

Section: Discussionmentioning

confidence: 99%

The Replicative Consequences of Papillomavirus E2 Protein Binding to the Origin Replication Factor ORC2

et al. 2016

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The origin recognition complex (ORC) coordinates a series of events that lead to initiation of DNA strand duplication. As a nuclear double stranded DNA plasmid, the papillomavirus (PV) genome resembles a mini-chromosome in infected cells. To initiate its replication, the viral E2 protein binds to and recruits the E1 DNA helicase at the viral origin. PV genome replication program exhibits three stages: initial amplification from a single genome upon infection to a few copies per cell, a cell cycle linked maintenance phase, and a differentiation dependent late stage where the genome is amplified to thousands of copies. Involvement of ORC or other pre-replication complex (pre-RC) factors has not been described. We report that human PV (HPV) and bovine PV (BPV-1) E2 proteins bind to ORC2, however, ORC2 was not detected at the viral origin. Depletion of ORC2 enhanced PV replication in a transient replication model and in keratinocytes stably maintaining viral episomes, while there was no effect on copy number in a cell line with integrated HPV genomes. Consistent with this, occupancy of E1 and E2 at the viral origin increased following ORC2 silencing. These data imply that ORC2 is not necessary for activation of the PV origin by E1 and E2 but instead suppresses E2 replicative function. Furthermore, we observed that over-expression of HPV E2 decreased ORC2 occupation at two known mammalian origins of replication, suggesting that E2 restricts pre-ORC assembly that could otherwise compete for host replication complexes necessary for viral genome amplification. We infer that the ORC2 complex with E2 restricts viral replication in the maintenance phase of the viral replication program and that elevated levels of E2 that occur during the differentiation dependent amplification stage subvert ORC loading and hence DNA synthesis at cellular origins.

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“…During the productive life cycle in stratified epithelia, HPV genomes undergo three distinct modes of replication [ 28 , 29 ]. During the first phase, shortly after initial entry into the nucleus, there is a rapid increase in viral genome DNA replication to increase the stable episome copy number.…”

Section: Modes Of Hpv Genome Replicationmentioning

confidence: 99%

“…The third phase of vegetative amplification is characterized by the rapid production of high numbers of viral genomes, where evidence has been seen for both bidirectional theta replication and recombination-dependent replication (RDR; [ 29 ]). RDR is a viral replication mechanism that lacks specific ORI sequences and that can initiate replication within various regions of the HPV genome.…”

Section: Modes Of Hpv Genome Replicationmentioning

confidence: 99%

Regulation of the Human Papillomavirus Life Cycle by DNA Damage Repair Pathways and Epigenetic Factors

Albert

Laimins

2020

Viruses

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Human papillomaviruses are the causative agents of cervical and other anogenital cancers along with approximately 60% of oropharyngeal cancers. These small double-stranded DNA viruses infect stratified epithelia and link their productive life cycles to differentiation. HPV proteins target cellular factors, such as those involved in DNA damage repair, as well as epigenetic control of host and viral transcription to regulate the productive life cycle. HPVs constitutively activate the ATM and ATR DNA repair pathways and preferentially recruit these proteins to viral genomes to facilitate productive viral replication. In addition, the sirtuin deacetylases along with histone acetyltransferases, including Tip60, are targeted in HPV infections to regulate viral transcription and replication. These pathways provide potential targets for drug therapy to treat HPV-induced disease.

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Initial amplification of the HPV18 genome proceeds via two distinct replication mechanisms

Cited by 24 publications

References 62 publications

Identification of several high-risk HPV inhibitors and drug targets with a novel high-throughput screening assay

Identification of several high-risk HPV inhibitors and drug targets with a novel high-throughput screening assay

The Replicative Consequences of Papillomavirus E2 Protein Binding to the Origin Replication Factor ORC2

Regulation of the Human Papillomavirus Life Cycle by DNA Damage Repair Pathways and Epigenetic Factors

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