Baculoviruses and Nucleosome Management

Virology 476 (2015) 257–263

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Virology

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Baculoviruses and nucleosome management

Loy E. Volkman 1,2

Department of Plant and Microbial Biology, University of California, Berkeley, CA 94720, USA article info abstract

Article history: Negatively-supercoiled-ds DNA molecules, including the genomes of baculoviruses, spontaneously wrap Received 5 November 2014 around cores of histones to form nucleosomes when present within eukaryotic nuclei. Hence, nucleosome Returned to author for revisions management should be essential for baculovirus genome replication and temporal regulation of transcrip- 9 December 2014 tion, but this has not been documented. Nucleosome mobilization is the dominion of ATP-dependent Accepted 10 December 2014 chromatin-remodeling complexes. SWI/SNF and INO80, two of the best-studied complexes, as well as chromatin modiﬁer TIP60, all contain actin as a subunit. Retrospective analysis of results of AcMNPV time Keywords: course experiments wherein actin polymerization was blocked by cytochalasin D drug treatment implicate Baculovirus actin-containing chromatin modifying complexes in decatenating baculovirus genomes, shutting down host AcMNPV transcription, and regulating late and very late phases of viral transcription. Moreover, virus-mediated Autographa californica M nuclear localization of actin early during infection may contribute to nucleosome management. nucleopolyhedrovirus & Nucleosomes 2014 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license Viral chromatin (http://creativecommons.org/licenses/by/3.0/). Actin-containing chromatin modiﬁcation complexes SWI/SNF, INO80, TIP60 Actin Topoisomerase 2 Negatively-supercoiled ds DNA

Introduction transcriptional level; that baculoviruses are the only nuclear replicating DNA viruses that use a combination of host and viral polymerases for The study of baculoviruses, pathogens of larval lepidopteran viral gene transcription; that TATA boxes and CAGT motifs promote insects, has been justified mainly by aims of improving their abilities transcription during the early phases, and that ATAAG, GTAAG or to serve humanity—as pesticides, expression vectors, vaccine plat- TTAAG motifs promote transcription during the late phases (Rohrmann, forms, drug therapy vectors and more (Moscardi, 1999; Chuang et al., 2013). Genome sequence has provided the basis for most baculovirus 2007; Airenne et al., 2013; Fernandes et al., 2013; Assenberg et al., studies conducted during the last several decades and a great deal has 2013; Contreras-Gomeź et al., 2013; Grabherr and Ernst, 2013; Van been learned. But baculoviruses, like papillomaviruses and polyoma- Oers et al., 2014). Investment in the utility of baculoviruses as viruses of vertebrates, have circular, negatively-supercoiled, double- laboratory tools and industrial workhorses has overshadowed invest- stranded (ds) DNA genomes, and any effect genome structure might ment in basic studies on how these viruses actually function. Auto- have on regulation of transcription and replication of baculoviruses has grapha californica multiple nucleopolyhedrovirus (AcMNPV) is the type yet to be explored. This omission in baculovirus lore may be attribu- species of the Alphabaculovirus genus of Baculoviridae and is the table to the influence of the long-standing view that DNA is a passive most-studied of the baculoviruses (Herniou et al., 2011). AcMNPV polymer bullied by proteins that dictate their interactions (Cozzarelli arguably has received more attention than any other insect virus that et al., 2006). This view has changed, however. DNA topologists have is not pathogenic for humans. Even so, large gaps remain in under- unequivocally demonstrated that DNA structure has an active role in standing the molecular strategies that AcMNPV and other baculo- regulating biological processes (Liu et al., 2009; Fogg et al., 2012). viruses use to reproduce and to make the cells they infect such Two lessons from DNA topology have immediate relevance for powerful protein expression machines. baculoviruses: (1) covalently-closed circular (ccc) supercoiled DNA The current paradigm holds that baculovirus gene expression replication results in intertwined rings of DNA that are decatenated occurs in four temporal phases and is regulated primarily at the in eukaryotes by topoisomerase 2 (Topo 2) (Liu et al., 2009); and (2) negatively-supercoiled DNA immediately forms nucleosomes on entering host nuclei making nucleosome manipulation essential both for baculovirus replication and temporal regulation of transcription E-mail address: [email protected] 1 Tel.: þ1 510 232 1305; Mobile: þ1 510 672 1894. (Patterton and von Holt, 1993; Baranello et al., 2012). To date, these 2 Permanent address: 6551 Arlington Blvd., Richmond, CA 94805, USA. principles have not been integrated into the baculovirus paradigm http://dx.doi.org/10.1016/j.virol.2014.12.022 0042-6822/& 2014 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/3.0/). 258 L.E. Volkman / Virology 476 (2015) 257–263 even though evidence that baculovirus genomic DNA is negatively complex is named after the primary ATPase that does the work. supercoiled has existed for decades. INO80 and SWI/SNF comprise two of the four main families of Models of negatively supercoiled ds DNA behavior abound (Witz these complexes. They are evolutionarily conserved from yeast and Stasiak, 2010). Chromosomal and plasmid DNA molecules are through vertebrates. These complexes are thought to have played negatively supercoiled in all bacteria, except for in extreme thermo- a major role in the evolution of multicellularity and the demand philes, giving DNA topologists and microbiologists ample material for tissue-specific and developmental-stage-specific expression of with which to study the properties of negatively supercoiled DNA in genes (Ho and Crabtree, 2010; Moshkin et al., 2012). biological systems (Schvartzman et al., 2013). Current evidence The ATP-dependent chromatin remodeling complexes consist of suggests that because torsional tension diminishes the DNA helicity 8–15 combinatorially assembled components with a core group and facilitates strand separation, negative supercoiling assists in DNA of essential subunits surrounded by others that, in vertebrates, at replication, transcription and aids DNA topoisomerases in decatenating least, switch in and out during specificstagesofdevelopmentand DNA. In short, negative supercoiling has emerged as a major factor in differentiation. All of the complexes are thought to have specialized, the governance of biological activities (Witz and Stasiak, 2010; non-redundant roles in development. Some of the complexes are cell- Schvartzman et al., 2013). type and developmental-stage specific(Ho and Crabtree, 2010). Use of a combinatorial complex for chromatin remodeling during develop- The AcMNPV genome is negatively supercoiled and forms ment and differentiation enables the formation of hundreds of nucleosomes complexes for diverse gene expression patterns (Moshkin et al., 2012). This wide selection of complexes could be vulnerable to intercep- Summers and Anderson (1973) used cesium chloride density tion and repurposing by negatively supercoiled viruses with nucleo- gradient centrifugation to show that baculovirus genomes consist some management issues of their own. Subunit modification or faux of ccc, supercoiled ds DNA. That the supercoiling is negative was subunit synthesis could be used to help recruit the ATP-dependent demonstrated by the rapid inactivation of baculoviruses by expo- complexes to viral chromatin for specific tasks. In this regard, it is sure to psoralens in 365 nm light (Hartig et al., 1992; Weightman worth noting that all group I NPVs have orthologs of SNF2 (Katsuma and Banks, 1999). Psoralens are bi-functional photoreactive mole- et al., 2008). SNF2 ATPases are the major ATPases in many SWI/SNF cules that preferentially intercalate into negatively supercoiled ds and INO80 chromatin-remodeling complexes. These ATPases have DNA and photoreact at 365 nm, forming cross-links between the active roles in both substrate recognition and catalytic activities apposing strands (Naughton et al., 2013; Kouzine et al., 2014). (Morrison and Shen, 2009). Moreover, during BmNPV infection of Wilson and Miller (1986) noted that parental AcMNPV DNA formed Bm5 cells, genes related to organism development are up-regulated chromatin-like structures within 2 h of uncoating within the nucleus, differentially throughout early, late and very late viral gene expression consistent with the properties of a negatively supercoiled ds DNA (Xue et al., 2012). molecule (Baranello et al., 2012). Additionally, treatment of DNA from infected cells with micrococcal nuclease resulted in monosome-sized fragments that contained both cellular and viral DNA. Extending these Actin-containing chromatin remodeling complexes findings, Wilson and Price (1988) observed that infection resulted in increased association of cellular histones with the nuclear matrix, and Actin is an abundant, conserved, 42 kDa ATPase that is regu- that progeny AcMNPV DNA incorporated histones prior to 24 hpi, all lated by a plethora of actin-binding proteins for many different supporting the idea that AcMNPV DNA forms nucleosomes in the cytoplasmic and nuclear functions (Krauss et al., 2003; Cisterna nucleus. et al., 2009; Visa and Percipalle, 2010; Simon and Wilson, 2011; Nucleosomes consist of 147 bp of DNA wrapped around a core Rajakylä and Vartiainen, 2014). Cytoplasmic functions of actin histone octamer, and these structures are spaced every 10 to 50 bp in inevitably depend on its ability to polymerize. Interestingly, this chromatin (Moshkin et al., 2012). Not surprisingly, they can impede activity may be dispensable for some nuclear functions (Posern access of DNA binding proteins to their target sequences, thereby et al., 2002; Johnson et al., 2013; Kapoor and Shen, 2014). preventing both transcription and replication. There is no basal Three of the best-studied families of chromatin-modifying transcription on cellular chromatin templates in vitro without factors complexes that contain actin as a monomeric subunit include mediating nucleosome repositioning or ejection (Moshkin et al., TIP60, INO80 and SWI/SNF (Olave et al., 2002; Morrison and Shen, 2012). Transcription takes place when AcMNPV chromatin templates 2009; Bartholomew, 2013; Kapoor and Shen, 2014). are transfected into susceptible host cells, however, showing the Histone acetyltransferase TIP60 (dTip60 in Drosophila) is part of a immediate early genes are open for business (Burand et al., 1980). multimeric protein complex that unites HAT with chromatin remodel- Chromatin-modifiers present within the transfected cells may have a ing activities that include both gene repression and activation. dTip60 role in immediate early gene transcription, but negative supercoiling is involved in widespread gene regulation in Drosophila, especially allows access to binding sites not available in positively supercoiled genes involved in chromatin-related functions (Schirling et al., 2010). or even neutral DNA (Baranello et al., 2012). Accordingly, transfection INO80 and SWI/SNF are ATP-dependent chromatin remodeling studies have shown that baculovirus genome replication is 4 times complexes that depend on their actin subunits to bind chromatin, and more efficient when the template is supercoiled than when it is thereby, to function (Zhao et al., 1998; Kapoor et al., 2013; Kapoor and nicked, and 15–150 times more efficient than when it is linearized Shen, 2014). INO80 figures prominently in transcriptional regulation, (Burand et al., 1980; Kitts et al., 1990). DNA replication and DNA repair (Morrison and Shen, 2009). The actin If negative supercoiling enables transcription of AcMNPV immedi- subunit in INO80 forms a module with actin-related proteins 4 and ate early genes and thereby offers a way out of nucleosomal con- 8 that interacts with chromatin during INO80-chromatin interaction straints, then subsequent viral transcriptional programs (delayed early, (Kapoor and Shen, 2014). Interestingly, actin may not have to retain late and very late) would be expected to depend on virus-encoded the ability to polymerize in order perform this function (Kapoor et al., factors capable of modulating chromosome-remodeling systems. 2013). The two SWI/SNF complexes in Drosophila are called Bhrama- Moving nucleosomes associated proteins (BAP) and polybromo-containing BAP (PBAP), and in vertebrates, BAF and PBAF (F for factors) (Fig. 1). BAP and PBAP are Nucleosome mobilization is the specialty of ATP-dependent both powered by Brahma (Brm), and each contains 11 subunits, 10 of chromatin remodeling complexes (Ho and Crabtree, 2010). Each which are identical. BAP and PBAP can serve as transcriptional L.E. Volkman / Virology 476 (2015) 257–263 259 activators or suppressors, and are known to interact with various apparent at 16 through 24 hpi. In the absence of CD, supercoils of transcription factors in different cell types. For example, BAP is control viral DNA firstappearedat12hpiandwereclearlypronounced essential for intestinal stem cell proliferation and damage-induced by16through24hpi.In1995,theseresultsweredifficult to explain, midgut regeneration in Drosophila (Jin et al., 2013). Notably, alphaba- but a recent study provides a plausible hypothesis. DNA topology rules culoviruses establish initial infection in differentiating larval lepidop- dictate that baculovirus DNA replication results in intertwined rings of teran midgut cells (Keddie et al., 1989; Washburn et al., 1995). Some DNA that are decatenated by Topo 2. Topo 2 needs BAF to mediate its studies have indicated that actin in SWI/SNF complexes needs to be binding to the chromatin matrix (Dykhuizen et al., 2013). If BAP, polymerizable to retain full function, but this point is still being debated (Randoetal.,2002;Zhao,etal.,1998).

Evidence for BAP and Topo 2 activity in baculovirus genome processing

The formation of baculovirus chromatin would seem to necessitate that both DNA replication and temporal regulation of transcription would involve the mobilization of nucleosomes, yet no studies have been conducted to test this possibility directly. Nonetheless, evidence from experiments conducted prior to the recognition of legitimate nuclear actin might shed some light on this topic. Actin was first shown to be essential for AcMNPV progeny production in 1987 when it was noted that cytochalasin D (CD), a drug that prevents actin polymerization, blocked nucleocapsid assembly in AcMNPV-infected cells (Volkman et al., 1987). These results were puzzling at the time because baculovirus nucleocapsid assembly takes place in the nucleus, and in 1987, actin was thought to function only in the cytoplasm. Nonetheless, the requirement for actin for progeny virus production was shown to be uniformly true for a wide variety of alphabaculoviruses infecting several different genera and species of cell lines (Kasman and Volkman, 2000). Viral DNA synthesis was not affected by CD, suggesting nucleosome mobilization for early gene expression and DNA replication do not depend on actin polymerization (Volkman, 1988). DNA processing Fig. 2. Reproduced from Oppenheimer (1995). Time course of viral DNA isolated was affected, however, as shown in time course experiments wherein from AcMNPV-infected Sf-21 cells grown in the absence (left) and presence (right) viral DNA was analyzed by field inversion gel electrophoresis of viral of cytochalasin D, resolved using field inversion gel electrophoresis, then probed 32 DNA (Fig. 2, Oppenheimer, 1995). Most of the viral DNA produced in with [ P]-dATP labeled total viral DNA as outlined in Oppenheimer and Volkman (1997). Times (hours) post infection when the samples were taken are indicated. the presence of CD remained stranded at the top of the gel, apparently DNA isolated from AcMNPV budded virus (BV) is shown on the left as a control for too large to penetrate, with very few individual supercoiled ccc forms supercoiled ccc DNA (runs at 1500 kb) and linear DNA at 134 kbp.

Fig. 1. Adapted and reprinted by permission from Macmillan Publishers Ltd: Nature, Ho, L., & Crabtree, G.R., 2010. Insect and vertebrate SWI/SNF complexes BAP and BAF, respectively. In the figure, homologous subunits are shown as similar shapes of the same color, allowing them to occupy specific positions in the illustrations. The various domains that enable the subunits to interact with DNA are depicted at the surface of each protein. Drosophila melanogaster has two SWI/SNF complexes—the Brahma (BRM)- associated proteins (BAP) complex, and the polybromo-containing BAP (PBAP) complex, and these can mediate transcriptional activation and transcription repression. In the figure, these are depicted collectively as BAP complexes. In the transition to vertebrate complexes, there was a large increase in the number of possible complexes. The possible subunits at each position are listed in the figure (for example, BAF60A, B, C indicates that one of these three subunits is present). Some assemblies of the vertebrate brahma-associated factor (BAF) complexes are tissue-specific and have unique developmental roles. Other assemblies might coexist in a specific cell type and perhaps target specific genes or function together with specific transcription factors. As in D. melanogaster, a second set of BAF complexes, the PBAF complexes, exists containing polybromo (also known as BAF 180). The fundamental activity of promoting nucleosome mobility has been highly conserved. BRD, bromodomain-containing protein; BRG1, brahma- related gene 1; MOR, Moira; PHD, plant homeodomain; PtdIns (4,5)P2, phosphatidylinositol-4,5-bisphosphate; SAYP, supporter of activation of yellow protein; SNR1, Snf5- related protein 1. 260 L.E. Volkman / Virology 476 (2015) 257–263 similarly, is needed to facilitate Topo 2 binding to viral chromatin for hypothesis, during BmNPV infection of Bm5 cells, genes related to genome processing, then CD might prevent processing by blocking organism development are up-regulated differentially throughout BAP binding and thereby mislocating Topo 2. early, late and very late viral gene expression (Xue et al., 2012).

Baculovirus-mediated nuclear localization of actin Evidence for actin-containing chromatin modifier-involvement During AcMNPV early gene expression, a considerable amount of in shut down of host transcription, and late and very late cytoplasmic monomeric actin is translocated to the nucleus and baculovirus transcription retained there (Ohkawa et al., 2002). Viral DNA transfection experiments revealed that five early genes of AcMNPV (in addition to the Late gene expression occurs coincident with viral DNA synth- ie0-ie1gene complex) appear to be involved in nuclear actin accumu- esis and the massive halt of most host transcription (Ooi and lation (Ohkawa et al., 2002). Ac004, Ac152,andpe38 transfected 1 day Miller,1988). According to DNA topology rules, all three of these prior to he65 and Ac102, leads to the nuclear localization of actin (NLA) processes should require nucleosome rearrangement (Fogg et al., (Ohkawa et al., 2002). In viral infection experiments, however, only 2012). Indeed, RNA silencing experiments targeting various one of the five viral genes, Ac102,isessentialforNLA.ThatAC102is AcMNPV-encoded late expression factors (lef-1, lef-2, lef-3 and needed for some other function(s) as well can be inferred from the lef-11), p143 or dnapol, showed each of them was essential for all failure of actin directed to the nucleus by an NLS motif to rescue an three processes (Schultz and Friesen, 2009). Moreover, Nagamine Ac102 deletion mutant (Gandhi et al., 2012). et al. (2008) showed that lef3 and p143 also were important for The nuclear localization of actin may be due, in part, to host heat host chromatin relocation to the nuclear margins, a cytopathic shock genes that are rapidly upregulated by 6 hpi, and are important effect that occurs during late gene expression in baculovirus- for DNA replication and baculovirus production (Salem et al., 2011; infected cells. Schultz and Friesen (2009) additionally showed that Lyupina et al., 2010). Heat shock is well known to promote nuclear when another group of AcMNPV-encoded factors (lef-8, lef-9, p47 translocation of actin (Iida et al. 1986; Johnson et al., 2013). and pp31) were silenced, only late gene expression was affected. Actin transcript levels do not increase during AcMNPV infection; All these factors are candidates for subverting ATP-dependent rather, the actin transcripts disappear at around 12 hpi along with chromatin remodeling complexes. transcripts of most other host genes (Ooi and Miller, 1988). Transcript The presence of CD in AcMNPV-infected cells delays virus- levels of other cytoskeletal elements, however, such as profilin, subunit induced shut-down of host protein synthesis (Talhouk and 4 of the Arp2/3 complex, and actin depolymerizing factor 1, do increase Volkman, 1991). It also leads to delays in the onset and shut- prior to 12 hpi in BmNPV-infected cells (Xue et al., 2012). down of late protein synthesis even though there is no change in Why would a virus cause such a massive shift in cytoplasmic timing or amount of viral DNA synthesized (Talhouk and Volkman, versus nuclear actin? The answer could be that the virus is repro- 1991; Volkman, 1988). Further, when CD is added to AcMNPV- gramming the host nucleus to a more embryonic state with incre- infected cells after host shut-down has occurred already, host asing concentrations of nuclear actin (Ho and Crabtree, 2010) mRNA and protein synthesis are revived, showing there is a (Fig. 3). Nuclear actin is known to play a major role in nuclear de- window of reversibility (Talhouk and Volkman, 1991). All these differentiation (Miyamoto and Gurdon, 2013). If the virus-induced observations could be explained if CD-sensitive chromatin modi- influx of monomeric actin triggers nuclear reprogramming, then fiers were involved in shutting down host protein synthesis and in viral late gene and very late gene expression could be regulated in transitioning between early and late phase of viral transcription. a manner similar to that of a differentiation pathway using virus- Again, candidates for recruiting these activities include lef-8, lef-9, modified chromatin remodeling complexes. Consistent with this p47 and pp31 (Schultz and Friesen, 2009).

Fig. 3. Reprinted by permission from Macmillan Publishers Ltd: Nature, Ho, L., & Crabtree, G.R., 2010. Embryonic stem cells (ESCs) are characterized by hyperdynamic chromatin, which is compacted when these cells exit from their pluripotent state and differentiate into cells of multiple lineages. In the self-renewing state, chromatin remodellers are required to prevent this chromatin compaction (CHD1) and to repress and reﬁne the inappropriate expression of genes (esBAF and the TIP-p400 complex) that would otherwise be allowed by the permissive chromatin landscape. Exit from this self-renewing state into a state that allows multilineage commitment involves global changes in chromatin conﬁguration, such as the formation of heterochromatin and the silencing of pluripotency genes (BAF complexes and NURD complexes). Evidence is emerging that chromatin remodellers such as BAF complexes are crucial for the reversal of development and the reactivation of pluripotency genes such as Oct 4, which occurs during the nuclear reprogramming of a committed cell type back into an ESC-like state. The proteins known to be involved are listed, together with the chromatin- remodelling complex they are found in (CHD, orange; SWI/SNF, green; ISWI, yellow; and INO80, pink). L.E. Volkman / Virology 476 (2015) 257–263 261

CD similarly delays the switch to the very late phase of transcrip- Vertebrate supercoiled ds DNA viruses and nucleosome tion (hyperexpression of polyhedrin and p10 mRNAs) but only when management present during the transitional period, 15–23 hpi (Wei and Volkman, 1992). Once the transition is passed and hyper-transcription has Papillomaviridae and Polyomaviridae are the only families among begun, addition of CD has no effect on p10 or polyhedrin mRNA nuclear-replicating, ds DNA vertebrate viruses known to have expression levels. If CD is added before the transition, recovery by negatively supercoiled, ccc genomes, assuring the formation of removing CD is possible but only if protein synthesis ensues (Wei and viral nucleosomes during infection. The genomes are small, 8 and Volkman, 1992). These results suggest that viral-encoded protein(s), 5 kb, respectively, and have only two phases of transcription: early such as VLF-1 (a known very late expression factor) and CD-sensitive and late. Both polyomaviruses and papillomaviruses have been chromatin modifiers are needed for the transition to hyperexpression studied extensively because of their cancer-causing capabilities to take place. (de Villiers et al., 2005; Hou et al., 2005). Their link with cancer likely involves their subversive effects on chromatin modifiers (Dhamne et al., 2007). fi Supercoiling and hyperexpression Papillomaviruses are more dif cult to study than polyomaviruses because of the lack of convenient cell culture systems that support The transition of oncogene c-myc from basal level to full level of their replication. Papillomaviruses infect basal epithelial cells but transcription is both BAF-regulated and dependent upon negative replicate only when the cells differentiate. This dependence on supercoiling (BrooksandHurley,2009;Baranelloetal.,2012). The differentiation could be mediated by the availability of appropriate SWI/SNF complexes are able to generate superhelical torsion in ATP-dependent chromatin-modifying complexes. U2OS cells, a cell nucleosome DNA (Olave et al., 2002). Upstream of the main promoter line established from bone tissue of a 15 yr old female osteosarcoma of c-myc is an AT-rich, supercoil-sensitive sequence called FUSE. In victim, will support genome replication when transfected with response to increasing levels of negative supercoiling, FUSE melts, papilloma virus genomes (Reinson et al., 2013). enabling binding of transcription activator FUSE-binding protein (FBP) Polyomaviruses, in comparison, are less demanding than papil- that increases the promoter activity and transcriptional rate to full lomaviruses. Even when susceptible host cells are quiescent, output (Fig. 4A) (Baranello et al., 2012; Kouzine et al., 2008). Similarly, polyomavirus can induce the synthesis of cellular DNA and cellular polyhedrin and p10 genes have AT-rich BURST sequences close to the enzymes related to DNA synthesis (Dulbecco, 1970). This capability transcription start sites that bind transcription activator VLF-1 (Kumar is remarkable because quiescent cells are devoid of nuclear actin, et al., 2009; Rohrmann, 2013). VLF-1 and the BURST sequences are which, in turn, reduces DNA synthesis and destabilizes the binding both known to promote hyperexpression (Rohrmann, 2013). VLF-1 of RNA polymerases II and III to their binding sites (Spencer et al., preferably binds cruciform structures, structures that are stabilized by 2011). The ease of establishing infection and replication in culture negative supercoiling (Mikhailov and Rohrmann, 2002). It is possible, helped to make SV40, type species of Polyomaviridae, the best- therefore, that c-myc, polyhedrin and p10 are similarly regulated studied negatively-supercoiled ds DNA virus of all. (Fig. 4A and B). For polyhedrin and P10 production, plenty of template ATP-dependent chromatin modifying complexes play pivotal is available. Only a small fraction of the replicated viral DNA is roles in SV40 replication and genome processing. Nucleosome encapsidated for virus assembly (2–4% for budded virus) and that positioning is critical for cleavage of SV40 chromatin by Topo 2 may account for the massive output in infected cells (Rohrmann, (Capranico et al., 1990; Ishimi et al., 1991; Halmer and Gruss, 1997). fi 2013). If, indeed, supercoiling is found to be involved in hyperexpres- Replication ef ciency of SV40 is linked directly to the accessibility sion of polyhedrin and p10, then baculoviruses could become valuable of topoisomerases I and II to the viral chromatin, which is, in turn, tools for elucidating the role(s) of host factors involved in regulating dependent on the overall chromatin structure (Halmer and Gruss, supercoiling and gene expression, important goals for cancer research 1997). Treatment of SV40-infected CV-1 cells with a Topo 2 cata- (Baranello et al., 2012). lytic inhibitor results in catenated dimers of genomic DNA that are resolved when the inhibitor is removed (Ishimi et al., 1995). In another example, SV40 DNA chromatin in Drosophila embryo extracts uses the chromatin-modifying complex CHRAC to alter the nucleosomal structure at the origin to enable access of the large T-antigen and efficient initiation of replication in the presence of ATP (Alexiadis et al., 1998). Infections by polyomaviruses and papillomaviruses induce double strand breaks and the DNA damage response (DDR) during genome replication and processing (Reinson et al., 2013; Dahl et al., 2005). Baculoviruses also induce the DDR during genome replication and processing;and,asitdoesforthepolyomavirusesandpapilloma- viruses, this response contributes to baculovirus production (Huang et al., 2011; Mitchell and Friesen, 2012; Mitchell et al., 2013). It should be noted that the DDR includes recruitment of chromatin-modifying complexes, which is favorable for viral DNA replication and processing (Morrison and Shen, 2009).

Fig. 4. Reprinted (A) and adapted (B) from Biochim. Biophys. Acta 1819, Baranello, L., et. al.. The importance of being supercoiled: How DNA mechanics regulate dynamic processes, pg 636, 2012, with permission from Elsevier. Regulation of Baculovirus ancestry c-myc compared to the potential regulation of AcMNPV polyhedrin and p10 genes. A. During transcription of c-myc, the melting of the supercoil-sensitive sequence There is no doubt that the era of DNA sequencing has led to a vast FUSE promotes the recruitment of factors that enhance (fuse-binding protein; FBP) trove of information that never would have been discovered any or repress (FBP-interacting repressor; FIR). B. Postulated mechanism of hyperex- other way. For insect virologists, the pay off included the discovery pression of AcMNPV polyhedrin and p10 genes. The AT-rich BURST sequence melts – enabling cruciform structures to form and bind VLG-1, leading to enhanced that baculoviruses, nudiviruses and bracoviruses three families of expression. insect viruses with different strategies for tracking and infecting 262 L.E. Volkman / Virology 476 (2015) 257–263 their hosts – are all genetically related (Wang et al., 2007; Cheng The author also thanks ExpressionSystems,LLC,Davis,CA,for et al., 2002; Bézier et al., 2009; Burand et al., 2012; Burke et al., financially supporting publication and open access of this article. 2013). Because bracovirus genomes are fully integrated into the DNA References of their mutualist partners, braconid parasitoid wasps, the three- virus-family phylogeny could be calibrated using the age of fossil Airenne, K.J., Hu, Y.C., Kost, T.A., Smith, R.H., Kotin, R.M., Ono, C., Matsuura, Y., Wang, S., amber-embedded wasps of the bracovirus-bearing microgastroid Yla-Herttuala, S., 2013. 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