Abstract
Animal and human papillomaviruses (HPVs) replicate persistently in specific types of stratified epithelia of their host. After the initial infection, the viral genome replicates at low levels in the dividing cells of the epithelium, and these cells form a reservoir of infection that can last for decades. When the infected cells differentiate, viral genomes replicate to high levels to form progeny virus that is released from the surface of the epithelium. This complex life cycle requires several different modes of viral DNA replication, but papillomaviruses are masters at hijacking key cellular processes to facilitate their own reproduction.
Papillomavirus genome structure and evolution
Papillomaviruses are an ancient group of viruses with small circular dsDNA genomes. They are ubiquitous and replicate in the mucosal and cutaneous stratified epithelium of hosts ranging from fish to humans (Van Doorslaer, 2013; Lopez-Bueno et al., 2016). To date, over 200 human papillomavirus (HPV), and about 140 animal papillomavirus types, have been described (https://pave.niaid.nih.gov; Van Doorslaer et al., 2017). Each papillomavirus has coevolved with its host for millions of years, and many have developed a predilection for specific cells or anatomical regions of the host epithelium. In some cases this niche adaptation has resulted in the development of viruses with oncogenic potential (Schiffman et al., 2016) Depending on the papillomavirus type and anatomical region of the host, infection can be asymptomatic, can result in a variety of warts or papillomas, or can lead to several types of cancer (Cubie, 2013; Schiffman et al., 2016). There is also evidence that some papillomavirus types can become truly latent (Doorbar, 2013).
The genome organization of all papillomaviruses is very similar; each viral genome consists of a 6–8 kb double-stranded circle of DNA (Figure 1) that encodes four core genes. The core proteins encoded by these genes are either structural, and form the viral capsid (L1 and L2), or are involved in viral DNA replication (E1 and E2). The remaining proteins, E4, E5, E6 and E7, are not encoded by all papillomaviruses and can be considered evolutionary embellishments. These proteins have important roles in adapting to specific host niches, in establishing a viral replication competent environment, in eluding the host immune system, and in modifying the host cell to facilitate release of progeny virion (Egawa et al., 2015). A fusion protein, E8^E2, is encoded by a spliced transcript and modulates viral replication and transcription. This is essential for the maintenance of the persistent, non-productive phase of infection (Dreer et al., 2016).
Human Papillomavirus (HPV) genome.
Shown is the circular dsDNA genome of an α-HPV. The core replication proteins, E1 and E2, are shown in dark cyan. The core structural proteins are shown in orange. URR, upstream regulatory region. PE and PL are the early and late promoters and pAE and pAL are the early and late polyadenylation sites. The replication origin is indicated.
Differentiation dependent papillomavirus infectious cycle and associated disease
Papillomaviruses have evolved an ingenious infectious cycle that takes advantage of the self-renewal process of stratified cutaneous and mucosal epithelia. In a stratified epithelium, the lower, basal layer of cells are attached to the basement membrane and they divide either symmetrically to generate more basal cells, or asymmetrically, in which case one of the daughter cells moves up towards the surface as part of the tissue renewal process. In the latter case, the cells move up through the epithelium, acquiring various characteristics of differentiation until they are sloughed from the surface of the tissue. Papillomaviruses take advantage of this process by infecting the basal cells through a fissure in the epithelium, and establishing a low level, persistent infection. The viral genome replicates extrachromosomally at a very low copy number in the basal cells, with minimal viral transcription. Then, when the infected cells transition through the differentiation process, high levels of viral DNA synthesis and gene expression takes place (Figure 2). This strategy helps the virus evade the immune system as high levels of viral activity occur only in terminally differentiated cells that are not subject to immune surveillance (Stanley, 2012).
Papillomavirus infectious cycle.
The schematic shows the differentiated layers of a stratified epithelium. HPV gains access to the basal cells of the epithelium through a fissure. Upon entry, the virus traffics through the endosome, becoming uncoated, but the viral genome (in complex with the L2 protein) must wait until the nuclear membrane breaks down in mitosis to gain entry to the nucleus. Once in the nucleus the viral genome undergoes a limited amplification and becomes established in the nucleus by attachment to host chromatin. The genome is maintained at a constant copy number in the dividing cells and is partitioned by the interaction with host chromatin. Upon differentiation, the infected cells amplify the viral DNA to high copy number, whereupon it is packaged into progeny viral particles. Virions are shed from the epithelium in viral-laden squames. At the top of the schematic, relative levels of viral DNA copy numbers are shown for each phases of viral DNA replication.
Modes of papillomavirus replication
The differentiation dependent life cycle of papillomaviruses ensures a stable, persistent infection, with a steady release of viral particles, but it means that the viral genome must be replicated by different mechanisms at different stages (reviewed in McBride, 2008). These stages are initial amplification, establishment, maintenance and vegetative amplification (Figure 2). When the virus first infects a basal keratinocyte, it must undergo a few rounds of DNA replication to generate a low copy number of viral genomes. Next, the viral genome must become established as a stably extrachromosomal replicon in a beneficial region of the host nucleus. The genomes are then maintained at a low, constant copy number and are partitioned to daughter cells upon cell division. The last stage is vegetative amplification, which occurs only in differentiated cells and generates high copy numbers of viral genomes that are destined to be packaged as progeny virions.
Viral replication proteins and replication origin
The conserved core proteins, E1 and E2, are both necessary and sufficient for papillomavirus replication (Ustav and Stenlund, 1991). These proteins cooperatively bind to specific binding sites in the replication origin to initiate replication (Ustav et al., 1991). E1 is an AAA + family helicase that binds and unwinds DNA to allow access of the cellular replicative machinery (Enemark and Joshua-Tor, 2006). E2 functions as a helicase loader to increase specificity, and facilitate binding of E1 to the replication origin (Stenlund, 2003). After formation of this replication initiation complex, E2 is displaced and E1 converts to hexameric helicases that bidirectionally unwind the replication origin (Stenlund, 2003; Enemark and Joshua-Tor, 2006). In addition to its role in initiation of replication, E2 facilitates maintenance and partitioning of the viral genome by tethering it to host chromatin (Skiadopoulos and McBride, 1998; Ilves et al., 1999). Very comprehensive reviews of the structure and function of the E1 and E2 proteins can be found in the Special Issue: The Papillomavirus Episteme (Bergvall et al., 2013; Lambert et al., 2013; McBride, 2013). The papillomavirus replication origin encompasses an E1 binding site, at least one E2 binding sites and an A/T rich region (Mohr et al., 1990; Ustav et al., 1991, 1993). Although one E2 binding site is often sufficient for initiation of replication, additional E2 sites will enhance this process (Remm et al., 1992; Russell and Botchan, 1995; Sun et al., 1996; Lee et al., 1997; McShan and Wilson, 1997). The detailed understanding of the interactions among viral and host replication proteins and the viral genome, make HPV replication an attractive target for anti-viral therapeutics (Archambault and Melendy, 2013).
Initial amplification of the viral genome
The papillomavirus virion contains two viral proteins, L1 and L2. L1 is the major structural protein that forms the capsid and L2, the minor capsid protein, is essential for early stages of infection, as well as packaging the viral genome into capsids at late stages of infection (Wang and Roden, 2013). Inside the viral particle, the genome is assembled with host histones into chromatin (Favre et al., 1977). Upon infection, the virus is trafficked through the endocytic pathways towards the nucleus, and the L1 capsid is removed during this process (Day et al., 2013). The viral minichromosome remains bound to L2, but the cell must proceed through mitosis (with concomitant nuclear envelope breakdown) before the L2-viral genome complex (still encased in membrane vesicles) can enter the nucleus (Pyeon et al., 2009; Aydin et al., 2014; DiGiuseppe et al., 2016). The L2-genome complex binds to the cellular condensed chromosomes, which ensures that the viral DNA is retained in the nucleus after mitosis (Aydin et al., 2014; DiGiuseppe et al., 2016).
Similar to many other DNA viruses, the L2-viral DNA complex is next observed adjacent to nuclear domain 10 (ND10) bodies (Day et al., 2004). These bodies are thought to be important for anti-viral defense, but also seem to be a location that is beneficial for early viral transcription and replication (Everett, 2006). L2 relocalizes the Sp100 and Daxx components of the ND10 body, to facilitate early viral transcription and replication of HPV DNA (Florin et al., 2002; Becker et al., 2003; Stepp et al., 2013). Transcripts encoding the E1 and E2 replication proteins are initiated by cellular factors (Ozbun, 2002; McKinney et al., 2016) to support the first stage of viral DNA replication.
The E1 and E2 proteins bind and unwind the replication origin, allowing cellular factors to synthesize, and amplify, the viral DNA (Mohr et al., 1990; Ustav and Stenlund, 1991; Ustav et al., 1991; McBride, 2008). This process amplifies viral DNA to a low copy number in the initial phases of infection, and this copy number is subsequently maintained in the dividing cells. The initial amplification of viral DNA signals a DNA damage response (DDR) in the host cells (C. McKinney and A. McBride, unpublished observations; Reinson et al., 2013), which must be tempered to allow the virus to switch to the quiescent, maintenance stage of persistent infection. Expression of the E8^E2 repressor protein is probably important at this stage to prevent runaway replication (Straub et al., 2014; Dreer et al., 2016).
Establishment, maintenance replication and genome partitioning
The establishment phase of replication is not well understood, but it is crucial to institute a persistent infection. Viral DNA must localize to beneficial regions of the nucleus, and escape anti-viral restriction mechanisms and epigenetic silencing (Porter et al., 2017). This is probably determined by early interactions of the viral DNA complex in the nucleus: the interaction of the L2 genome complex with host mitotic chromosomes; the interaction of the L2 genome complex with ND10 bodies; and the subsequent association of the viral DNA and E2 protein with host chromatin (see below).
The E1 and E2 proteins initiate replication from the viral replication origin, but this is not sufficient for long-term, maintenance replication. Viral genomes replicate at a constant copy number, but also need also to be efficiently partitioned to daughter cells. At least six additional E2 binding sites, located in the URR of the bovine papillomavirus type 1 (BPV1) genome, are required for maintenance of the viral genome as an extrachromosomal element (Piirsoo et al., 1996). This requirement was explained by the finding that papillomavirus genomes, and the viral E2 protein, are bound to host mitotic chromosomes in dividing cells (Skiadopoulos and McBride, 1998; Ilves et al., 1999). The N-terminal transactivation domain of the E2 protein interacts with host chromatin, while the DNA binding domain binds to sites in the viral genome (Bastien and McBride, 2000). The partitioning model has been best characterized for BPV1, which contains many E2 binding sites in the URR (Figure 3B), and whose E2 protein binds host chromosomes with high affinity. Most likely, all papillomaviruses have a comparable tethering strategy, though differences must exist. For example, most α-HPV genomes have only four E2 binding sites in the URR, and two of these binding sites are sufficient to segregate HPV18-derived plasmids in the absence of replication (Ustav et al., 2015). Additionally, not all papillomavirus E2 proteins associate with host chromosomes at the same location, or with high affinity (McPhillips et al., 2006; Oliveira et al., 2006). However, E2 proteins that do not associate with host chromatin when expressed alone, will associate tightly when coexpressed with the E1 protein (Sakakibara et al., 2013a; Jang et al., 2014).
Replication proteins and origin of replication.
(A) E1 and E2 proteins. The E2 proteins consist of two conserved structural and functional domains linked by a less well-conserved and flexible, hinge region. The N-terminal domain is important for transcriptional regulation, interaction with the E1 protein, and tethering to host chromatin. The C-terminal domain is a sequence specific dimeric DNA binding domain. The E8^E2 repressor protein is encoded by a spliced transcript that fuses a short peptide from E8 fused to the hinge and DNA binding domain of E2. The E1 protein contains four structural domains. Phosphorylation of multiple sites in the N-terminal domain regulates nuclear-cytoplasmic transport. E1 also contains a sequence specific origin binding domain, and an oligomerization domain that promotes the formation of hexamers. The C-terminal domain is a AAA + family helicase. (B) The upstream regulatory region (URR) of HPV18 (an α-HPV) and BPV1 (a δ-HPV). pAL is the late polyadenylation site. The numbered cyan circles are E2 binding sites and the orange rectangle if the E1 binding site. The end of the L1 and beginning of the E6 open reading frames are shown in pale orange. The papillomavirus replication origin encompasses an E1 binding site, at least one E2 binding site and an A/T rich region.
There has been great interest in identifying the host chromatin protein(s) to which the viral E2-genome complex is tethered. In theory, disruption of this interaction would result in loss of viral genomes and resolution of persistent infection. Several cellular proteins are candidates for the host chromatin target that mediates partitioning of HPV genomes (reviewed in McBride, 2013). For example, cellular proteins TopBP1 and ChlR1 have been have been implicated in various stages of the establishment and maintenance process (Parish et al., 2006; Donaldson et al., 2012; Gauson et al., 2015; Kanginakudru et al., 2015; Harris et al., 2017). A highly studied, though still controversial, target is the cellular chromatin protein, Brd4. Brd4 is a double bromodomain protein that binds to acetylated histones, regulates transcriptional initiation and elongation, and serves as a mitotic bookmark (reviewed in McBride and Jang, 2013; Iftner et al., 2016). Brd4 interacts with all papillomavirus E2 proteins to regulate viral transcription (You et al., 2004; McPhillips et al., 2006; Wu et al., 2006; Schweiger et al., 2007; Smith et al., 2010; Rahman et al., 2011), and E2 proteins that bind Brd4 with high affinity (such as BPV1) stabilize its association on host chromatin (You et al., 2004; Baxter et al., 2005; McPhillips et al., 2005). However, many HPV E2s are only observed associated with host chromatin using techniques such as bimolecular fluorescence complementation (Helfer et al., 2013) or when E2 is highly expressed. Also, and HPV31 genomes that express a Brd4 binding defective E2 protein are still maintained extrachromosomally (Stubenrauch et al., 1998; Senechal et al., 2007), indicating that the role of Brd4 as the main chromosomal target is complex. Nevertheless, Brd4 is involved in almost every step of the viral infectious cycle: Brd4 activates early viral transcription upon infection (McKinney et al., 2016), and later, in complex with E2 represses viral transcription (Wu et al., 2006; Smith et al., 2010; Rahman et al., 2011). Brd4 is also observed localized to replication foci that form later in infection (Sakakibara et al., 2013a; Wang et al., 2013; Gauson et al., 2015).
The interaction of papillomavirus genomes with host chromatin is important for more than just partitioning of viral DNA during cell division. Association of viral DNA with transcriptionally active regions of host chromatin will facilitate viral transcription (Jang et al., 2009; Helfer et al., 2014). Likewise, complexes of HPV1 E2/Brd4 (or HPV16 E1/E2/Brd4) bind to host chromatin at common fragile sites, which are regions of the host genome that are susceptible to replication stress (Jang et al., 2014). This association could facilitate the development of DDR-dependent replication foci for late amplification of viral DNA (see below).
Vegetative viral replication and papillomavirus replication foci
In the differentiated cells of a stratified epithelium, the viral genome undergoes a second amplification. Quantitative analysis in lesions caused by OcPV1 (ROPV, or rabbit oral papillomavirus) show a five log increase in viral genomes upon late amplification (Maglennon et al., 2011). This is concomitant with high levels of the E1 and E2 proteins and activation of the late promoter (Klumpp and Laimins, 1999). A pivotal study showed that the cellular DDR is activated by the viral E7 protein, and this is essential for late genome amplification (Moody and Laimins, 2009).
Similar to many other DNA viruses, viral DNA replication takes place in nuclear foci and components of the DDR pathway are recruited here (Fradet-Turcotte et al., 2011; Sakakibara et al., 2011; Gillespie et al., 2012; Reinson et al., 2013). These replication compartments are very similar to the nuclear foci that form upon cellular DNA damage. DNA damage foci form around breaks in cellular DNA, or at collapsed replication forks, and induce signaling pathways that arrest cell growth, and recruit factors to repair damaged DNA (McKinney et al., 2015). HPVs mimic DNA damage and induce the DDR pathways, resulting in an influx of factors that can replicate viral DNA. Current thinking is that viral DNA is replicated in differentiated cells by a recombination-dependent replication (RDR) mode supported by the DDR response (Sakakibara et al., 2013b; Gautam and Moody, 2016). This would be advantageous, as HPVs are thought to amplify their viral DNA in differentiated cells in the G2 phase of the cell cycle, and so lack the S-phase replication machinery (Nakahara et al., 2005; Banerjee et al., 2011). Many viruses encode recombinases, single-stranded DNA binding proteins, exonucleases and resolvases to facilitate viral genome replication by RDR (Lo Piano et al., 2011). However, HPVs must induce similar cellular factors through DDR signaling and repair pathways to support RDR. RDR is unidirectional and origin independent, and can efficiently synthesize large amounts of concatemeric DNA. It is probable that cellular repair factors can resolve these structures into monomeric, circular genomes. However, the exact mechanisms of recombination-mediated replication must still be elucidated (Orav et al., 2015).
As mentioned above, HPV replication proteins complex with Brd4 and associate with regions of the host genome that are susceptible to replication stress (Jang et al., 2014). Furthermore, viral replication foci often develop adjacent to these regions. This association could facilitate DDR signaling and recruitment of factors that support the development of DDR-dependent replication foci for late amplification of viral DNA.
Viral genome integration
Occasionally, papillomavirus genomes are found integrated into the host genome, and this is particularly notable with oncogenic HPVs (Schwarz et al., 1985). In many HPV-associated cancers, the viral genome is integrated in such a way as to deregulate expression of the E6/E7 oncogenes, which leads to genomic instability and carcinogenic progression (McBride and Warburton, 2017). Many cellular processes are hijacked and manipulated during papillomavirus infection; viral DNA replication engages the DNA damage response (Moody and Laimins, 2009; Sakakibara et al., 2011; Reinson et al., 2013; Anacker and Moody, 2017), and viral genomes must tether to viral chromatin to ensure that they persist, and are partitioned, in proliferating cells (Skiadopoulos and McBride, 1998; Ilves et al., 1999; Bastien and McBride, 2000). It is advantageous for papillomavirus genome to tether to transcriptionally active regions of the host genome (Jang et al., 2009; Helfer et al., 2014), and to replicate adjacent to regions undergoing replication stress (Jang et al., 2014). Localization to these regions ensures that the viral genome remains transcriptionally active, and also has easy access to factors that mediate DNA synthesis. HPV replication foci form adjacent to common fragile sites (regions undergoing replication stress), and this correlates with the observation that oncogenic HPVs are often found integrated in these regions (Thorland et al., 2000; Jang et al., 2014; Gao et al., 2017). However, integration is not part of the papillomavirus life cycle, but is an accidental ‘dead-end’ that eliminates the potential of viral progeny production.
Summary
Papillomaviruses have evolved highly specific viral-host interactions to facilitate viral DNA replication. The biochemical mechanisms and protein interactions required for viral DNA synthesis are well understood, and most current studies focus on host pathways and interactions that are manipulated and hijacked by the virus to replicate in the different cellular environments of a stratified epithelium. Despite the remarkable advances that have been made in understanding HPV replication processes, papillomaviruses still have much to teach us about the biology of their host.
Acknowledgments
Alison McBride’s research is supported by the Intramural Research Program of the NIAID (Grant/Award Number: ‘ZIA AI001073’), NIH.
References
Anacker, D.C. and Moody, C.A. (2017). Modulation of the DNA damage response during the life cycle of human papillomaviruses. Virus Res. 231, 41–49.10.1016/j.virusres.2016.11.006Search in Google Scholar
Archambault, J. and Melendy, T. (2013). Targeting human papillomavirus genome replication for antiviral drug discovery. Antivir. Ther. 18, 271–283.10.3851/IMP2612Search in Google Scholar
Aydin, I., Weber, S., Snijder, B., Samperio Ventayol, P., Kuhbacher, A., Becker, M., Day, P.M., Schiller, J.T., Kann, M., Pelkmans, L., et al. (2014). Large scale RNAi reveals the requirement of nuclear envelope breakdown for nuclear import of human papillomaviruses. PLoS Pathog. 10, e1004162.10.1371/journal.ppat.1004162Search in Google Scholar
Banerjee, N.S., Wang, H.K., Broker, T.R., and Chow, L.T. (2011). Human papillomavirus (HPV) E7 induces prolonged G2 following S phase reentry in differentiated human keratinocytes. J. Biol. Chem. 286, 15473–15482.10.1074/jbc.M110.197574Search in Google Scholar
Bastien, N. and McBride, A.A. (2000). Interaction of the papillomavirus E2 protein with mitotic chromosomes. Virology 270, 124–134.10.1006/viro.2000.0265Search in Google Scholar
Baxter, M.K., McPhillips, M.G., Ozato, K., and McBride, A.A. (2005). The mitotic chromosome binding activity of the papillomavirus E2 protein correlates with interaction with the cellular chromosomal protein, Brd4. J. Virol. 79, 4806–4818.10.1128/JVI.79.8.4806-4818.2005Search in Google Scholar
Becker, K.A., Florin, L., Sapp, C., and Sapp, M. (2003). Dissection of human papillomavirus type 33 L2 domains involved in nuclear domains (ND) 10 homing and reorganization. Virology 314, 161–167.10.1016/S0042-6822(03)00447-1Search in Google Scholar
Bergvall, M., Melendy, T., and Archambault, J. (2013). The E1 proteins. Virology 445, 35–56.10.1016/j.virol.2013.07.020Search in Google Scholar PubMed PubMed Central
Cubie, H.A. (2013). Diseases associated with human papillomavirus infection. Virology 445, 21–34.10.1016/j.virol.2013.06.007Search in Google Scholar PubMed
Day, P.M., Baker, C.C., Lowy, D.R., and Schiller, J.T. (2004). Establishment of papillomavirus infection is enhanced by promyelocytic leukemia protein (PML) expression. Proc. Natl. Acad Sci. USA 101, 14252–14257.10.1073/pnas.0404229101Search in Google Scholar PubMed PubMed Central
Day, P.M., Thompson, C.D., Schowalter, R.M., Lowy, D.R., and Schiller, J.T. (2013). Identification of a role for the trans-Golgi network in human papillomavirus 16 pseudovirus infection. J. Virol. 87, 3862–3870.10.1128/JVI.03222-12Search in Google Scholar PubMed PubMed Central
DiGiuseppe, S., Luszczek, W., Keiffer, T.R., Bienkowska-Haba, M., Guion, L.G., and Sapp, M.J. (2016). Incoming human papillomavirus type 16 genome resides in a vesicular compartment throughout mitosis. Proc. Natl. Acad Sci. USA 113, 6289–6294.10.1073/pnas.1600638113Search in Google Scholar PubMed PubMed Central
Donaldson, M.M., Mackintosh, L.J., Bodily, J.M., Dornan, E.S., Laimins, L.A., and Morgan, I.M. (2012). An interaction between human papillomavirus 16 E2 and TopBP1 is required for optimum viral DNA replication and episomal genome establishment. J. Virol. 86, 12806–12815.10.1128/JVI.01002-12Search in Google Scholar PubMed PubMed Central
Doorbar, J. (2013). Latent papillomavirus infections and their regulation. Curr. Opin. Virol. 3, 416–421.10.1016/j.coviro.2013.06.003Search in Google Scholar PubMed
Dreer, M., van de Poel, S., and Stubenrauch, F. (2016). Control of viral replication and transcription by the papillomavirus E8^E2 protein. Virus Res. 231, 96–102.10.1016/j.virusres.2016.11.005Search in Google Scholar PubMed
Egawa, N., Egawa, K., Griffin, H., and Doorbar, J. (2015). Human papillomaviruses; epithelial tropisms, and the development of neoplasia. Viruses 7, 3863–3890.10.3390/v7072802Search in Google Scholar PubMed PubMed Central
Enemark, E.J. and Joshua-Tor, L. (2006). Mechanism of DNA translocation in a replicative hexameric helicase. Nature 442, 270–275.10.1038/nature04943Search in Google Scholar PubMed
Everett, R.D. (2006). Interactions between DNA viruses, ND10 and the DNA damage response. Cell. Microbiol. 8, 365–374.10.1111/j.1462-5822.2005.00677.xSearch in Google Scholar PubMed
Favre, M., Breitburd, F., Croissant, O., and Orth, G. (1977). Chromatin-like structures obtained after alkaline disruption of bovine and human papillomaviruses. J. Virol. 21, 1205–1209.10.1128/jvi.21.3.1205-1209.1977Search in Google Scholar
Florin, L., Schafer, F., Sotlar, K., Streeck, R.E., and Sapp, M. (2002). Reorganization of nuclear domain 10 induced by papillomavirus capsid protein l2. Virology 295, 97–107.10.1006/viro.2002.1360Search in Google Scholar PubMed
Fradet-Turcotte, A., Bergeron-Labrecque, F., Moody, C.A., Lehoux, M., Laimins, L.A., and Archambault, J. (2011). Nuclear accumulation of the papillomavirus E1 helicase blocks S-phase progression and triggers an ATM-dependent DNA damage response. J. Virol. 85, 8996–9012.10.1128/JVI.00542-11Search in Google Scholar PubMed PubMed Central
Gao, G., Johnson, S.H., Vasmatzis, G., Pauley, C.E., Tombers, N.M., Kasperbauer, J.L., and Smith, D.I. (2017). Common fragile sites (CFS) and extremely large CFS genes are targets for human papillomavirus integrations and chromosome rearrangements in oropharyngeal squamous cell carcinoma. Genes Chromosomes Cancer 56, 59–74.10.1002/gcc.22415Search in Google Scholar PubMed
Gauson, E.J., Donaldson, M.M., Dornan, E.S., Wang, X., Bristol, M., Bodily, J.M., and Morgan, I.M. (2015). Evidence supporting a role for TopBP1 and Brd4 in the initiation but not continuation of human papillomavirus 16 E1/E2-mediated DNA replication. J. Virol. 89, 4980–4991.10.1128/JVI.00335-15Search in Google Scholar PubMed PubMed Central
Gautam, D. and Moody, C.A. (2016). Impact of the DNA damage response on human papillomavirus chromatin. PLoS Pathog 12, e1005613.10.1371/journal.ppat.1005613Search in Google Scholar PubMed PubMed Central
Gillespie, K.A., Mehta, K.P., Laimins, L.A., and Moody, C.A. (2012). Human papillomaviruses recruit cellular DNA repair and homologous recombination factors to viral replication centers. J. Virol. 86, 9520–9526.10.1128/JVI.00247-12Search in Google Scholar PubMed PubMed Central
Harris, L., McFarlane-Majeed, L., Campos-Leon, K., Roberts, S., and Parish, J.L. (2017). The cellular DNA helicase ChlR1 regulates chromatin and nuclear matrix attachment of the human papillomavirus 16 E2 protein and high-copy-number viral genome establishment. J. Virol. 91, e01853-16.10.1128/JVI.01853-16Search in Google Scholar PubMed PubMed Central
Helfer, C.M., Wang, R., and You, J. (2013). Analysis of the papillomavirus E2 and bromodomain protein Brd4 interaction using bimolecular fluorescence complementation. PLoS One 8, e77994.10.1371/journal.pone.0077994Search in Google Scholar PubMed PubMed Central
Helfer, C.M., Yan, J., and You, J. (2014). The cellular bromodomain protein Brd4 has multiple functions in E2-mediated papillomavirus transcription activation. Viruses 6, 3228–3249.10.3390/v6083228Search in Google Scholar PubMed PubMed Central
Iftner, T., Haedicke-Jarboui, J., Wu, S.Y., and Chiang, C.M. (2016). Involvement of Brd4 in different steps of the papillomavirus life cycle. Virus Res. 231, 76–82.10.1016/j.virusres.2016.12.006Search in Google Scholar PubMed PubMed Central
Ilves, I., Kivi, S., and Ustav, M. (1999). Long-term episomal maintenance of bovine papillomavirus type 1 plasmids is determined by attachment to host chromosomes, which is mediated by the viral E2 protein and its binding sites. J. Virol. 73, 4404–4412.10.1128/JVI.73.5.4404-4412.1999Search in Google Scholar PubMed PubMed Central
Jang, M.K., Kwon, D., and McBride, A.A. (2009). Papillomavirus E2 proteins and the host BRD4 protein associate with transcriptionally active cellular chromatin. J. Virol. 83, 2592–2600.10.1128/JVI.02275-08Search in Google Scholar
Jang, M.K., Shen, K., and McBride, A.A. (2014). Papillomavirus genomes associate with BRD4 to replicate at fragile sites in the host genome. PLoS Pathog. 10, e1004117.10.1371/journal.ppat.1004117Search in Google Scholar
Kanginakudru, S., DeSmet, M., Thomas, Y., Morgan, I.M., and Androphy, E.J. (2015). Levels of the E2 interacting protein TopBP1 modulate papillomavirus maintenance stage replication. Virology 478, 129–135.10.1016/j.virol.2015.01.011Search in Google Scholar
Klumpp, D.J. and Laimins, L.A. (1999). Differentiation-induced changes in promoter usage for transcripts encoding the human papillomavirus type 31 replication protein E1. Virology 257, 239–246.10.1006/viro.1999.9636Search in Google Scholar
Lambert, P.F., McBride, A., and Bernard, H.U. (2013). Special issue: The papillomavirus episteme. Virology 445, 1–1.10.1016/j.virol.2013.07.017Search in Google Scholar
Lee, D., Kim, H., Lee, Y., and Choe, J. (1997). Identification of sequence requirement for the origin of DNA replication in human papillomavirus type 18. Virus Res 52, 97–108.10.1016/S0168-1702(97)00114-7Search in Google Scholar
Lo Piano, A., Martinez-Jimenez, M.I., Zecchi, L., and Ayora, S. (2011). Recombination-dependent concatemeric viral DNA replication. Virus Res 160, 1–14.10.1016/j.virusres.2011.06.009Search in Google Scholar
Lopez-Bueno, A., Mavian, C., Labella, A.M., Castro, D., Borrego, J.J., Alcami, A., and Alejo, A. (2016). Concurrence of iridovirus, polyomavirus, and a unique member of a new group of fish papillomaviruses in lymphocystis disease-affected gilthead sea bream. J. Virol. 90, 8768–8779.10.1128/JVI.01369-16Search in Google Scholar
Maglennon, G.A., McIntosh, P., and Doorbar, J. (2011). Persistence of viral DNA in the epithelial basal layer suggests a model for papillomavirus latency following immune regression. Virology 414, 153–163.10.1016/j.virol.2011.03.019Search in Google Scholar
McBride, A.A. (2008). Replication and partitioning of papillomavirus genomes. Adv. Virus Res. 72, 155–205.10.1016/S0065-3527(08)00404-1Search in Google Scholar
McBride, A.A. (2013). The papillomavirus E2 proteins. Virology 445, 57–79.10.1016/j.virol.2013.06.006Search in Google Scholar PubMed PubMed Central
McBride, A.A. and Jang, M.K. (2013). Current understanding of the role of the Brd4 protein in the papillomavirus lifecycle. Viruses 5, 1374–1394.10.3390/v5061374Search in Google Scholar PubMed PubMed Central
McBride, A.A. and Warburton, A. (2017). The Role of Integration in Oncogenic Progression of HPV associated cancers. PLos Pathog. 13, e1006211.10.1371/journal.ppat.1006211Search in Google Scholar PubMed PubMed Central
McKinney, C.C., Hussmann, K.L., and McBride, A.A. (2015). The role of the DNA damage response throughout the papillomavirus life cycle. Viruses 7, 2450–2469.10.3390/v7052450Search in Google Scholar PubMed PubMed Central
McKinney, C.C., Kim, M.J., Chen, D., and McBride, A.A. (2016). Brd4 activates early viral transcription upon human papillomavirus 18 infection of primary keratinocytes. mBio 7, e01644–16.10.1128/mBio.01644-16Search in Google Scholar PubMed PubMed Central
McPhillips, M.G., Ozato, K., and McBride, A.A. (2005). Interaction of bovine papillomavirus E2 protein with Brd4 stabilizes its association with chromatin. J. Virol. 79, 8920–8932.10.1128/JVI.79.14.8920-8932.2005Search in Google Scholar PubMed PubMed Central
McPhillips, M.G., Oliveira, J.G., Spindler, J.E., Mitra, R., and McBride, A.A. (2006). Brd4 is required for e2-mediated transcriptional activation but not genome partitioning of all papillomaviruses. J. Virol. 80, 9530–9543.10.1128/JVI.01105-06Search in Google Scholar PubMed PubMed Central
McShan, G.D. and Wilson, V.G. (1997). Reconstitution of a functional bovine papillomavirus type 1 origin of replication reveals a modular tripartite replicon with an essential AT-rich element. Virology 237, 198–208.10.1006/viro.1997.8793Search in Google Scholar PubMed
Mohr, I.J., Clark, R., Sun, S., Androphy, E.J., MacPherson, P., and Botchan, M.R. (1990). Targeting the E1 replication protein to the papillomavirus origin of replication by complex formation with the E2 transactivator. Science 250, 1694–1699.10.1126/science.2176744Search in Google Scholar PubMed
Moody, C.A. and Laimins, L.A. (2009). Human papillomaviruses activate the ATM DNA damage pathway for viral genome amplification upon differentiation. PLoS Pathog 5, e1000605.10.1371/journal.ppat.1000605Search in Google Scholar PubMed PubMed Central
Nakahara, T., Peh, W.L., Doorbar, J., Lee, D., and Lambert, P.F. (2005). Human papillomavirus type 16 E1^E4 contributes to multiple facets of the papillomavirus life cycle. J. Virol. 79, 13150–13165.10.1128/JVI.79.20.13150-13165.2005Search in Google Scholar PubMed PubMed Central
Oliveira, J.G., Colf, L.A., and McBride, A.A. (2006). Variations in the association of papillomavirus E2 proteins with mitotic chromosomes. Proc. Natl. Acad. Sci. USA 103, 1047–1052.10.1073/pnas.0507624103Search in Google Scholar PubMed PubMed Central
Orav, M., Geimanen, J., Sepp, E.M., Henno, L., Ustav, E., and Ustav, M. (2015). Initial amplification of the HPV18 genome proceeds via two distinct replication mechanisms. Sci. Rep. 5, 15952.10.1038/srep15952Search in Google Scholar PubMed PubMed Central
Ozbun, M.A. (2002). Human papillomavirus type 31b infection of human keratinocytes and the onset of early transcription. J. Virol. 76, 11291–11300.10.1128/JVI.76.22.11291-11300.2002Search in Google Scholar PubMed PubMed Central
Parish, J.L., Bean, A.M., Park, R.B., and Androphy, E.J. (2006). ChlR1 Is required for loading papillomavirus E2 onto mitotic chromosomes and viral genome maintenance. Mol. Cell 24, 867–876.10.1016/j.molcel.2006.11.005Search in Google Scholar PubMed
Piirsoo, M., Ustav, E., Mandel, T., Stenlund, A., and Ustav, M. (1996). Cis and trans requirements for stable episomal maintenance of the BPV-1 replicator. EMBO J. 15, 1–11.10.1002/j.1460-2075.1996.tb00328.xSearch in Google Scholar
Porter, S.S., Stepp, W.H., Stamos, J.D., and McBride, A.A. (2017). Host cell restriction factors that limit transcription and replication of human papillomavirus. Virus Res. 231, 10–20.10.1016/j.virusres.2016.11.014Search in Google Scholar PubMed PubMed Central
Pyeon, D., Pearce, S.M., Lank, S.M., Ahlquist, P., and Lambert, P.F. (2009). Establishment of human papillomavirus infection requires cell cycle progression. PLoS Pathog. 5, e1000318.10.1371/journal.ppat.1000318Search in Google Scholar PubMed PubMed Central
Rahman, S., Sowa, M.E., Ottinger, M., Smith, J.A., Shi, Y., Harper, J.W., and Howley, P.M. (2011). The Brd4 extraterminal domain confers transcription activation independent of pTEFb by recruiting multiple proteins, including NSD3. Mol. Cell Biol. 31, 2641–2652.10.1128/MCB.01341-10Search in Google Scholar PubMed PubMed Central
Reinson, T., Toots, M., Kadaja, M., Pipitch, R., Allik, M., Ustav, E., and Ustav, M. (2013). Engagement of the ATR-dependent DNA damage response at the human papillomavirus 18 replication centers during the initial amplification. J. Virol. 87, 951–964.10.1128/JVI.01943-12Search in Google Scholar PubMed PubMed Central
Remm, M., Brain, R., and Jenkins, J.R. (1992). The E2 binding sites determine the efficiency of replication for the origin of human papillomavirus type 18. Nucleic Acids Res. 20, 6015–6021.10.1093/nar/20.22.6015Search in Google Scholar PubMed PubMed Central
Russell, J. and Botchan, M.R. (1995). cis-Acting components of human papillomavirus (HPV) DNA replication: linker substitution analysis of the HPV type 11 origin. J. Virol. 69, 651–660.10.1128/jvi.69.2.651-660.1995Search in Google Scholar PubMed PubMed Central
Sakakibara, N., Mitra, R., and McBride, A.A. (2011). The papillomavirus E1 helicase activates a cellular DNA damage response in viral replication foci. J. Virol. 85, 8981–8995.10.1128/JVI.00541-11Search in Google Scholar PubMed PubMed Central
Sakakibara, N., Chen, D., Jang, M.K., Kang, D.W., Luecke, H.F., Wu, S.Y., Chiang, C.M., and McBride, A.A. (2013a). Brd4 is displaced from HPV replication factories as they expand and amplify viral DNA. PLoS Pathog. 9, e1003777.10.1371/journal.ppat.1003777Search in Google Scholar PubMed PubMed Central
Sakakibara, N., Chen, D., and McBride, A.A. (2013b). Papillomaviruses use recombination-dependent replication to vegetatively amplify their genomes in differentiated cells. PLoS Pathog. 9, e1003321.10.1371/journal.ppat.1003321Search in Google Scholar PubMed PubMed Central
Schiffman, M., Doorbar, J., Wentzensen, N., de Sanjose, S., Fakhry, C., Monk, B.J., Stanley, M.A., and Franceschi, S. (2016). Carcinogenic human papillomavirus infection. Nature reviews. Dis. Primers 2, 16086.10.1038/nrdp.2016.86Search in Google Scholar PubMed
Schwarz, E., Freese, U.K., Gissmann, L., Mayer, W., Roggenbuck, B., Stremlau, A., and zur Hausen, H. (1985). Structure and transcription of human papillomavirus sequences in cervical carcinoma cells. Nature 314, 111–114.10.1038/314111a0Search in Google Scholar PubMed
Schweiger, M.R., Ottinger, M., You, J., and Howley, P.M. (2007). Brd4 independent transcriptional repression function of the papillomavirus E2 proteins. J. Virol. 81, 9612–9622.10.1128/JVI.00447-07Search in Google Scholar PubMed PubMed Central
Senechal, H., Poirier, G.G., Coulombe, B., Laimins, L.A., and Archambault, J. (2007). Amino acid substitutions that specifically impair the transcriptional activity of papillomavirus E2 affect binding to the long isoform of Brd4. Virology 358, 10–17.10.1016/j.virol.2006.08.035Search in Google Scholar PubMed
Skiadopoulos, M.H. and McBride, A.A. (1998). Bovine papillomavirus type 1 genomes and the E2 transactivator protein are closely associated with mitotic chromatin. J. Virol. 72, 2079–2088.10.1128/JVI.72.3.2079-2088.1998Search in Google Scholar PubMed PubMed Central
Smith, J.A., White, E.A., Sowa, M.E., Powell, M.L., Ottinger, M., Harper, J.W., and Howley, P.M. (2010). Genome-wide siRNA screen identifies SMCX, EP400, and Brd4 as E2-dependent regulators of human papillomavirus oncogene expression. Proc. Natl. Acad Sci. USA 107, 3752–3757.10.1073/pnas.0914818107Search in Google Scholar PubMed PubMed Central
Stanley, M.A. (2012). Epithelial cell responses to infection with human papillomavirus. Clinical microbiology reviews 25, 215–222.10.1128/CMR.05028-11Search in Google Scholar PubMed PubMed Central
Stenlund, A. (2003). Initiation of DNA replication: lessons from viral initiator proteins. Nat. Rev. Mol. Cell Biol. 4, 777–785.10.1038/nrm1226Search in Google Scholar PubMed
Stepp, W.H., Meyers, J.M., and McBride, A.A. (2013). Sp100 provides intrinsic immunity against human papillomavirus infection. mBio 4, e00845–00813.10.1128/mBio.00845-13Search in Google Scholar PubMed PubMed Central
Straub, E., Dreer, M., Fertey, J., Iftner, T., and Stubenrauch, F. (2014). The viral E8^E2C repressor limits productive replication of human papillomavirus 16. J. Virol. 88, 937–947.10.1128/JVI.02296-13Search in Google Scholar PubMed PubMed Central
Stubenrauch, F., Colbert, A.M., and Laimins, L.A. (1998). Transactivation by the E2 protein of oncogenic human papillomavirus type 31 is not essential for early and late viral functions. J. Virol. 72, 8115–8123.10.1128/JVI.72.10.8115-8123.1998Search in Google Scholar PubMed PubMed Central
Sun, Y.N., Lu, J.Z., and McCance, D.J. (1996). Mapping of HPV-11 E1 binding site and determination of other important cis elements for replication of the origin. Virology 216, 219–222.10.1006/viro.1996.0050Search in Google Scholar PubMed
Thorland, E.C., Myers, S.L., Persing, D.H., Sarkar, G., McGovern, R.M., Gostout, B.S., and Smith, D.I. (2000). Human papillomavirus type 16 integrations in cervical tumors frequently occur in common fragile sites. Cancer Res. 60, 5916–5921.Search in Google Scholar
Ustav, M. and Stenlund, A. (1991). Transient replication of BPV-1 requires two viral polypeptides encoded by the E1 and E2 open reading frames. EMBO J. 10, 449–457.10.1002/j.1460-2075.1991.tb07967.xSearch in Google Scholar PubMed PubMed Central
Ustav, M., Ustav, E., Szymanski, P., and Stenlund, A. (1991). Identification of the origin of replication of bovine papillomavirus and characterization of the viral origin recognition factor E1. EMBO J. 10, 4321–4329.10.1002/j.1460-2075.1991.tb05010.xSearch in Google Scholar PubMed PubMed Central
Ustav, E., Ustav, M., Szymanski, P., and Stenlund, A. (1993). The bovine papillomavirus origin of replication requires a binding site for the E2 transcriptional activator. Proc. Natl. Acad Sci. USA 90, 898–902.10.1073/pnas.90.3.898Search in Google Scholar PubMed PubMed Central
Ustav, M., Jr., Castaneda, F.R., Reinson, T., Mannik, A., and Ustav, M. (2015). Human papillomavirus type 18 cis-elements crucial for segregation and latency. PLoS One 10, e0135770.10.1371/journal.pone.0135770Search in Google Scholar
Van Doorslaer, K. (2013). Evolution of the papillomaviridae. Virology 445, 11–20.10.1016/j.virol.2013.05.012Search in Google Scholar
Van Doorslaer, K., Li, Z., Xirasagar, S., Maes, P., Kaminsky, D., Liou, D., Sun, Q., Kaur, R., Huyen, Y., and McBride, A.A. (2017). The Papillomavirus Episteme: a major update to the papillomavirus sequence database. Nucleic Acids Res. 45, D499–D506.10.1093/nar/gkw879Search in Google Scholar
Wang, J.W. and Roden, R.B. (2013). L2, the minor capsid protein of papillomavirus. Virology 445, 175–186.10.1016/j.virol.2013.04.017Search in Google Scholar
Wang, X., Helfer, C.M., Pancholi, N., Bradner, J.E., and You, J. (2013). Recruitment of Brd4 to the human papillomavirus type 16 DNA replication complex is essential for replication of viral DNA. J. Virol. 87, 3871–3884.10.1128/JVI.03068-12Search in Google Scholar
Wu, S.Y., Lee, A.Y., Hou, S.Y., Kemper, J.K., Erdjument-Bromage, H., Tempst, P., and Chiang, C.M. (2006). Brd4 links chromatin targeting to HPV transcriptional silencing. Genes Dev. 20, 2383–2396.10.1101/gad.1448206Search in Google Scholar
You, J., Croyle, J.L., Nishimura, A., Ozato, K., and Howley, P.M. (2004). Interaction of the bovine papillomavirus E2 protein with Brd4 tethers the viral DNA to host mitotic chromosomes. Cell 117, 349–360.10.1016/S0092-8674(04)00402-7Search in Google Scholar
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