Human bocavirus 1 (HBoV1) belongs to the genus Bocaparvovirus of the Parvoviridae family, and is an emerging human pathogenic respiratory virus. In vitro, HBoV1 infects well-differentiated/polarized primary human airway epithelium (HAE) cultured at an air-liquid interface (HAE-ALI). Although it is well known that autonomous parvovirus replication depends on the S phase of the host cells, we demonstrate here that the HBoV1 genome amplifies efficiently in mitotically quiescent airway epithelial cells of HAE-ALI cultures. Analysis of HBoV1 DNA in infected HAE-ALI revealed that HBoV1 amplifies its ssDNA genome following a typical parvovirus rolling-hairpin DNA replication mechanism. Notably, HBoV1 infection of HAE-ALI initiates a DNA damage response (DDR) with activation of all three phosphatidylinositol 3-kinase–related kinases (PI3KKs). We found that the activation of the three PI3KKs is required for HBoV1 genome amplification; and, more importantly, we identified that two Y-family DNA polymerases, Pol η and Pol κ, are involved in HBoV1 genome amplification. Overall, we have provided an example of de novo DNA synthesis (genome amplification) of an autonomous parvovirus in non-dividing cells, which is dependent on the cellular DNA damage and repair pathways.
References
[1]
Allander T, Tammi MT, Eriksson M, Bjerkner A, Tiveljung-Lindell A, Andersson B (2005) Cloning of a human parvovirus by molecular screening of respiratory tract samples. Proc Natl Acad Sci U S A 102: 12891–12896. pmid:16118271 doi: 10.1073/pnas.0504666102
[2]
Cotmore SF, Agbandje-McKenna M, Chiorini JA, Mukha DV, Pintel DJ, Qiu J, Soderlund-Venermo M, Tattersall P, Tijssen P, Gatherer D, Davison AJ (2014) The family Parvoviridae. Arch Virol 159: 1239–1247. doi: 10.1007/s00705-013-1914-1. pmid:24212889
[3]
Allander T, Jartti T, Gupta S, Niesters HG, Lehtinen P, Osterback R, Vuorinen T, Waris M, Bjerkner A, Tiveljung-Lindell A, van den Hoogen BG, Hyypia T, Ruuskanen O (2007) Human bocavirus and acute wheezing in children. Clin Infect Dis 44: 904–910. pmid:17342639 doi: 10.1086/512196
[4]
Meriluoto M, Hedman L, Tanner L, Simell V, Makinen M, Simell S, Mykkanen J, Korpelainen J, Ruuskanen O, Ilonen J, Knip M, Simell O, Hedman K, Soderlund-Venermo M (2012) Association of Human Bocavirus 1 Infection with Respiratory Disease in Childhood Follow-up Study, Finland. Emerg Infect Dis 18: 264–271. doi: 10.3201/eid1802.111293. pmid:22305021
[5]
Kantola K, Hedman L, Allander T, Jartti T, Lehtinen P, Ruuskanen O, Hedman K, Soderlund-Venermo M (2008) Serodiagnosis of human bocavirus infection. Clin Infect Dis 46: 540–546. doi: 10.1086/526532. pmid:18199037
[6]
Don M, Soderlund-Venermo M, Valent F, Lahtinen A, Hedman L, Canciani M, Hedman K, Korppi M (2010) Serologically verified human bocavirus pneumonia in children. Pediatr Pulmonol 45: 120–126. doi: 10.1002/ppul.21151. pmid:19960524
[7]
Nascimento-Carvalho CM, Cardoso MR, Meriluoto M, Kemppainen K, Kantola K, Ruuskanen O, Hedman K, Soderlund-Venermo M (2012) Human bocavirus infection diagnosed serologically among children admitted to hospital with community-acquired pneumonia in a tropical region. J Med Virol 84: 253–258. doi: 10.1002/jmv.22268. pmid:22170545
[8]
Christensen A, Nordbo SA, Krokstad S, Rognlien AG, Dollner H (2010) Human bocavirus in children: mono-detection, high viral load and viraemia are associated with respiratory tract infection. J Clin Virol 49: 158–162. doi: 10.1016/j.jcv.2010.07.016. pmid:20833582
[9]
Soderlund-Venermo M, Lahtinen A, Jartti T, Hedman L, Kemppainen K, Lehtinen P, Allander T, Ruuskanen O, Hedman K (2009) Clinical assessment and improved diagnosis of bocavirus-induced wheezing in children, Finland. Emerg Infect Dis 15: 1423–1430. doi: 10.3201/eid1509.090204. pmid:19788810
[10]
Christensen A, D？llner H, Shanke LH, Krokstad S, Moe N, Nordb？ SA (2013) Detection of spliced mRNA from human bocavirus 1 in clinical samples from children with respiratory tract infections. Emerg Infect Dis 19: 574–580. doi: 10.3201/eid1904.121775. pmid:23628409
[11]
Ursic T, Steyer A, Kopriva S, Kalan G, Krivec U, Petrovec M (2011) Human bocavirus as the cause of a life-threatening infection. J Clin Microbiol 49: 1179–1181. doi: 10.1128/JCM.02362-10. pmid:21227992
[12]
Dijkman R, Koekkoek SM, Molenkamp R, Schildgen O, van der Hoek L (2009) Human bocavirus can be cultured in differentiated human airway epithelial cells. J Virol 83: 7739–7748. doi: 10.1128/JVI.00614-09. pmid:19474096
[13]
Villenave R, Thavagnanam S, Sarlang S, Parker J, Douglas I, Skibinski G, Heaney LG, McKaigue JP, Coyle PV, Shields MD, Power UF (2012) In vitro modeling of respiratory syncytial virus infection of pediatric bronchial epithelium, the primary target of infection in vivo. Proc Natl Acad Sci U S A 109: 5040–5045. doi: 10.1073/pnas.1110203109. pmid:22411804
[14]
Pickles RJ (2013) Human airway epithelial cell cultures for modeling respiratory syncytial virus infection. Curr Top Microbiol Immunol 372: 371–387. doi: 10.1007/978-3-642-38919-1_19. pmid:24362700
[15]
Kotha PL, Sharma P, Kolawole AO, Yan R, Alghamri MS, Brockman TL, Gomez-Cambronero J, Excoffon KJ (2015) Adenovirus entry from the apical surface of polarized epithelia is facilitated by the host innate immune response. PLoS Pathog 11: e1004696. doi: 10.1371/journal.ppat.1004696. pmid:25768646
[16]
Huang Q, Deng X, Yan Z, Cheng F, Luo Y, Shen W, Lei-Butters DC, Chen AY, Li Y, Tang L, Soderlund-Venermo M, Engelhardt JF, Qiu J (2012) Establishment of a reverse genetics system for studying human bocavirus in human airway epithelia. PLoS Pathog 8: e1002899. doi: 10.1371/journal.ppat.1002899. pmid:22956907
[17]
Deng X, Yan Z, Luo Y, Xu J, Cheng Y, Li Y, Engelhardt J, Qiu J (2013) In vitro modeling of human bocavirus 1 infection of polarized primary human airway epithelia. J Virol 87: 4097–4102. doi: 10.1128/JVI.03132-12. pmid:23345515
[18]
Martin ET, Kuypers J, McRoberts JP, Englund JA, Zerr DM (2015) Human Bocavirus-1 Primary Infection and Shedding in Infants. J Infect Dis 212: 516–524. doi: 10.1093/infdis/jiv044. pmid:25632039
[19]
Bashir T, Horlein R, Rommelaere J, Willwand K (2000) Cyclin A activates the DNA polymerase delta -dependent elongation machinery in vitro: A parvovirus DNA replication model. Proc Natl Acad Sci U S A 97: 5522–5527. pmid:10792046 doi: 10.1073/pnas.090485297
[20]
Bashir T, Rommelaere J, Cziepluch C (2001) In vivo accumulation of cyclin A and cellular replication factors in autonomous parvovirus minute virus of mice-associated replication bodies. J Virol 75: 4394–4398. pmid:11287588 doi: 10.1128/jvi.75.9.4394-4398.2001
[21]
Cotmore SF, Tattersall P (1987) The autonomously replicating parvoviruses of vertebrates. Adv Virus Res 33: 91–174. pmid:3296697 doi: 10.1016/s0065-3527(08)60317-6
[22]
Bern KI, Parsons MJ (2015) Parvoviridae. In: Kinpe DM, Howley PM, editors. Fields Virology. Philadelphia: Lippincott Williams & Wilkins. pp. 1768–1791.
Coats S, Flanagan WM, Nourse J, Roberts JM (1996) Requirement of p27Kip1 for restriction point control of the fibroblast cell cycle. Science 272: 877–880. pmid:8629023 doi: 10.1126/science.272.5263.877
[25]
Prosperi E (1997) Multiple roles of the proliferating cell nuclear antigen: DNA replication, repair and cell cycle control. Prog Cell Cycle Res 3: 193–210. pmid:9552415 doi: 10.1007/978-1-4615-5371-7_15
[26]
Scholzen T, Gerdes J (2000) The Ki-67 protein: from the known and the unknown. J Cell Physiol 182: 311–322. pmid:10653597 doi: 10.1002/(sici)1097-4652(200003)182:3<311::aid-jcp1>3.0.co;2-9
[27]
Shen W, Deng X, Zou W, Cheng F, Engelhardt JF, Yan Z, Qiu J (2015) Identification and Functional Analysis of Novel Non-structural Proteins of Human Bocavirus 1. J Virol 89: 10097–10109. doi: 10.1128/JVI.01374-15. pmid:26223640
[28]
Luo Y, Deng X, Cheng F, Li Y, Qiu J (2013) SMC1-mediated intra-S phase arrest facilitates Bocavirus DNA replication. J Virol 87: 4017–4032. doi: 10.1128/JVI.03396-12. pmid:23365434
[29]
Cotmore SF, Tattersall P (2005) A rolling-haipin strategy: basic mechanisms of DNA replication in the parvoviruses. In: Kerr J, Cotmore SF, Bloom ME, Linden RM, Parrish CR, editors. Parvoviruses. London: Hoddler Arond. pp. 171–181.
[30]
Strzalka W, Ziemienowicz A (2011) Proliferating cell nuclear antigen (PCNA): a key factor in DNA replication and cell cycle regulation. Ann Bot 107: 1127–1140. doi: 10.1093/aob/mcq243. pmid:21169293
[31]
Block WD, Yu Y, Lees-Miller SP (2004) Phosphatidyl inositol 3-kinase-like serine/threonine protein kinases (PIKKs) are required for DNA damage-induced phosphorylation of the 32 kDa subunit of replication protein A at threonine 21. Nucleic Acids Res 32: 997–1005. pmid:14872059 doi: 10.1093/nar/gkh265
[32]
Mah LJ, El-Osta A, Karagiannis TC (2010) gammaH2AX: a sensitive molecular marker of DNA damage and repair. Leukemia 24: 679–686. doi: 10.1038/leu.2010.6. pmid:20130602
[33]
Bakkenist CJ, Kastan MB (2003) DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation. Nature 421: 499–506. pmid:12556884 doi: 10.1038/nature01368
[34]
Liu S, Shiotani B, Lahiri M, Marechal A, Tse A, Leung CC, Glover JN, Yang XH, Zou L (2011) ATR autophosphorylation as a molecular switch for checkpoint activation. Mol Cell 43: 192–202. doi: 10.1016/j.molcel.2011.06.019. pmid:21777809
[35]
Yajima H, Lee KJ, Zhang S, Kobayashi J, Chen BP (2009) DNA double-strand break formation upon UV-induced replication stress activates ATM and DNA-PKcs kinases. J Mol Biol 385: 800–810. doi: 10.1016/j.jmb.2008.11.036. pmid:19071136
[36]
Golding SE, Rosenberg E, Valerie N, Hussaini I, Frigerio M, Cockcroft XF, Chong WY, Hummersone M, Rigoreau L, Menear KA, O'Connor MJ, Povirk LF, van MT, Valerie K (2009) Improved ATM kinase inhibitor KU-60019 radiosensitizes glioma cells, compromises insulin, AKT and ERK prosurvival signaling, and inhibits migration and invasion. Mol Cancer Ther 8: 2894–2902. doi: 10.1158/1535-7163.MCT-09-0519. pmid:19808981
[37]
Gonzalez-Mariscal L, Betanzos A, Nava P, Jaramillo BE (2003) Tight junction proteins. Prog Biophys Mol Biol 81: 1–44. pmid:12475568
[38]
Foote KM, Blades K, Cronin A, Fillery S, Guichard SS, Hassall L, Hickson I, Jacq X, Jewsbury PJ, McGuire TM, Nissink JW, Odedra R, Page K, Perkins P, Suleman A, Tam K, Thommes P, Broadhurst R, Wood C (2013) Discovery of 4-{4-[(3R)-3-Methylmorpholin-4-yl]-6-[1-(methylsulfonyl)cyclopropyl]pyrimidin-2-y l}-1H-indole (AZ20): a potent and selective inhibitor of ATR protein kinase with monotherapy in vivo antitumor activity. J Med Chem 56: 2125–2138. doi: 10.1021/jm301859s. pmid:23394205
[39]
Arris CE, Boyle FT, Calvert AH, Curtin NJ, Endicott JA, Garman EF, Gibson AE, Golding BT, Grant S, Griffin RJ, Jewsbury P, Johnson LN, Lawrie AM, Newell DR, Noble ME, Sausville EA, Schultz R, Yu W (2000) Identification of novel purine and pyrimidine cyclin-dependent kinase inhibitors with distinct molecular interactions and tumor cell growth inhibition profiles. J Med Chem 43: 2797–2804. pmid:10956187 doi: 10.1021/jm990628o
[40]
Cotmore SF, Tattersall P (2014) Parvoviruses: Small Does Not Mean Simple. Annu Rev Virol 1: 517–537. doi: 10.1146/annurev-virology-031413-085444
[41]
Samulski RJ, Muzyczka N (2014) AAV-Mediated Gene Therapy for Research and Therapeutic Purposes. Annu Rev Virol 1: 427–451. doi: 10.1146/annurev-virology-031413-085355
[42]
Hubscher U, Maga G, Spadari S (2002) Eukaryotic DNA polymerases. Annu Rev Biochem 71: 133–163. pmid:12045093 doi: 10.1146/annurev.biochem.71.090501.150041
[43]
An P, Saenz Robles MT, Pipas JM (2012) Large T antigens of polyomaviruses: amazing molecular machines. Annu Rev Microbiol 66: 213–236. doi: 10.1146/annurev-micro-092611-150154. pmid:22994493
[44]
Wallace NA, Galloway DA (2014) Manipulation of cellular DNA damage repair machinery facilitates propagation of human papillomaviruses. Semin Cancer Biol 26: 30–42. doi: 10.1016/j.semcancer.2013.12.003. pmid:24412279
[45]
Moody CA, Laimins LA (2009) Human papillomaviruses activate the ATM DNA damage pathway for viral genome amplification upon differentiation. PLoS Pathog 5: e1000605. doi: 10.1371/journal.ppat.1000605. pmid:19798429
[46]
Sakakibara N, Chen D, McBride AA (2013) Papillomaviruses use recombination-dependent replication to vegetatively amplify their genomes in differentiated cells. PLoS Pathog 9: e1003321. doi: 10.1371/journal.ppat.1003321. pmid:23853576
[47]
Luo Y, Chen AY, Qiu J (2011) Bocavirus infection induces a DNA damage response that facilitates viral DNA replication and mediates cell death. J Virol 85: 133–145. doi: 10.1128/JVI.01534-10. pmid:21047968
[48]
Luo Y, Lou S, Deng X, Liu Z, Li Y, Kleiboeker S, Qiu J (2011) Parvovirus B19 infection of human primary erythroid progenitor cells triggers ATR-Chk1 signaling, which promotes B19 virus replication. J Virol 85: 8046–8055. doi: 10.1128/JVI.00831-11. pmid:21680529
[49]
Adeyemi RO, Landry S, Davis ME, Weitzman MD, Pintel DJ (2010) Parvovirus minute virus of mice induces a DNA damage response that facilitates viral replication. PLoS Pathog 6: e1001141. doi: 10.1371/journal.ppat.1001141. pmid:20949077
[50]
Ruiz Z, Mihaylov IS, Cotmore SF, Tattersall P (2011) Recruitment of DNA replication and damage response proteins to viral replication centers during infection with NS2 mutants of Minute Virus of Mice (MVM). Virology 410: 375–384. doi: 10.1016/j.virol.2010.12.009. pmid:21193212
[51]
Cotmore SF, Tattersall P (2013) Parvovirus diversity and DNA damage responses. Cold Spring Harb Perspect Biol 5: a012989. doi: 10.1101/cshperspect.a012989. pmid:23293137
[52]
Luo Y, Qiu J (2013) Parvovirus infection induced DNA damage response. Future Virol 8: 245–257. pmid:25429305 doi: 10.2217/fvl.13.5
[53]
Luo Y, Kleiboeker S, Deng X, Qiu J (2013) Human parvovirus B19 infection causes cell cycle arrest of human erythroid progenitors at late S phase that favors viral DNA replication. J Virol 87: 12766–12775. doi: 10.1128/JVI.02333-13. pmid:24049177
[54]
Schwartz RA, Carson CT, Schuberth C, Weitzman MD (2009) Adeno-associated virus replication induces a DNA damage response coordinated by DNA-dependent protein kinase. J Virol 83: 6269–6278. doi: 10.1128/JVI.00318-09. pmid:19339345
[55]
Vogel R, Seyffert M, Strasser R, de Oliveira AP, Dresch C, Glauser DL, Jolinon N, Salvetti A, Weitzman MD, Ackermann M, Fraefel C (2012) Adeno-Associated Virus Type 2 Modulates the Host DNA Damage Response Induced by Herpes Simplex Virus 1 during Coinfection. J Virol 86: 143–155. doi: 10.1128/JVI.05694-11. pmid:22013059
[56]
Jurvansuu J, Raj K, Stasiak A, Beard P (2005) Viral transport of DNA damage that mimics a stalled replication fork. J Virol 79: 569–580. pmid:15596849 doi: 10.1128/jvi.79.1.569-580.2005
[57]
Flotte TR, Afione SA, Zeitlin PL (1994) Adeno-associated virus vector gene expression occurs in nondividing cells in the absence of vector DNA integration. Am J Respir Cell Mol Biol 11: 517–521. pmid:7946381 doi: 10.1165/ajrcmb.11.5.7946381
[58]
Alexander IE, Russell DW, Miller AD (1994) DNA-damaging agents greatly increase the transduction of nondividing cells by adeno-associated virus vectors. J Virol 68: 8282–8287. pmid:7966621
[59]
Yalkinoglu AO, Heilbronn R, Burkle A, Schlehofer JR, zur HH (1988) DNA amplification of adeno-associated virus as a response to cellular genotoxic stress. Cancer Res 48: 3123–3129. pmid:2835153
[60]
Shiotani B, Zou L (2009) Single-stranded DNA orchestrates an ATM-to-ATR switch at DNA breaks. Mol Cell 33: 547–558. doi: 10.1016/j.molcel.2009.01.024. pmid:19285939
[61]
Yang W (2014) An overview of Y-Family DNA polymerases and a case study of human DNA polymerase eta. Biochemistry 53: 2793–2803. doi: 10.1021/bi500019s. pmid:24716551
[62]
Haracska L, Prakash L, Prakash S (2002) Role of human DNA polymerase kappa as an extender in translesion synthesis. Proc Natl Acad Sci U S A 99: 16000–16005. pmid:12444249 doi: 10.1073/pnas.252524999
[63]
Masuda Y, Kanao R, Kaji K, Ohmori H, Hanaoka F, Masutani C (2015) Different types of interaction between PCNA and PIP boxes contribute to distinct cellular functions of Y-family DNA polymerases. Nucleic Acids Res doi: 10.1093/nar/gkv712.
[64]
Gillespie KA, Mehta KP, Laimins LA, Moody CA (2012) Human papillomaviruses recruit cellular DNA repair and homologous recombination factors to viral replication centers. J Virol 86: 9520–9526. doi: 10.1128/JVI.00247-12. pmid:22740399
Duan D, Sharma P, Yang J, Yue Y, Dudus L, Zhang Y, Fisher KJ, Engelhardt JF (1998) Circular intermediates of recombinant adeno-associated virus have defined structural characteristics responsible for long-term episomal persistence in muscle tissue. J Virol 72: 8568–8577. pmid:9765395
Inagaki K, Ma C, Storm TA, Kay MA, Nakai H (2007) The role of DNA-PKcs and artemis in opening viral DNA hairpin termini in various tissues in mice. J Virol 81: 11304–11321. pmid:17686847 doi: 10.1128/jvi.01225-07
[69]
Baldauf AQ, Willwand K, Mumtsidu E, Nuesch JP, Rommelaere J (1997) Specific initiation of replication at the right-end telomere of the closed species of minute virus of mice replicative-form DNA. J Virol 71: 971–980. pmid:8995615
[70]
Choi YK, Nash K, Byrne BJ, Muzyczka N, Song S (2010) The effect of DNA-dependent protein kinase on adeno-associated virus replication. PLoS ONE 5: e15073. doi: 10.1371/journal.pone.0015073. pmid:21188139
[71]
Meyers C, Mane M, Kokorina N, Alam S, Hermonat PL (2000) Ubiquitous human adeno-associated virus type 2 autonomously replicates in differentiating keratinocytes of a normal skin model. Virology 272: 338–346. pmid:10873777 doi: 10.1006/viro.2000.0385
[72]
Liu X, Ory V, Chapman S, Yuan H, Albanese C, Kallakury B, Timofeeva OA, Nealon C, Dakic A, Simic V, Haddad BR, Rhim JS, Dritschilo A, Riegel A, McBride A, Schlegel R (2012) ROCK inhibitor and feeder cells induce the conditional reprogramming of epithelial cells. Am J Pathol 180: 599–607. doi: 10.1016/j.ajpath.2011.10.036. pmid:22189618
[73]
Hirt B (1967) Selective extraction of polyoma DNA from infected mouse cell cultures. J Mol Biol 26: 365–369. pmid:4291934 doi: 10.1016/0022-2836(67)90307-5
[74]
Guan W, Cheng F, Yoto Y, Kleiboeker S, Wong S, Zhi N, Pintel DJ, Qiu J (2008) Block to the production of full-length B19 virus transcripts by internal polyadenylation is overcome by replication of the viral genome. J Virol 82: 9951–9963. doi: 10.1128/JVI.01162-08. pmid:18684834
[75]
Sowd GA, Li NY, Fanning E (2013) ATM and ATR activities maintain replication fork integrity during SV40 chromatin replication. PLoS Pathog 9: e1003283. doi: 10.1371/journal.ppat.1003283. pmid:23592994
[76]
Chen AY, Guan W, Lou S, Liu Z, Kleiboeker S, Qiu J (2010) Role of Erythropoietin Receptor Signaling in Parvovirus B19 Replication in Human Erythroid Progenitor Cells. J Virol 84: 12385–12396. doi: 10.1128/JVI.01229-10. pmid:20861249
[77]
Chen AY, Cheng F, Lou S, Luo Y, Liu Z, Delwart E, Pintel D, Qiu J (2010) Characterization of the gene expression profile of human bocavirus. Virology 403: 145–154. doi: 10.1016/j.virol.2010.04.014. pmid:20457462
[78]
Ariumi Y, Turelli P, Masutani M, Trono D (2005) DNA damage sensors ATM, ATR, DNA-PKcs, and PARP-1 are dispensable for human immunodeficiency virus type 1 integration. J Virol 79: 2973–2978. pmid:15709017 doi: 10.1128/jvi.79.5.2973-2978.2005
[79]
Vidal-Eychenie S, Decaillet C, Basbous J, Constantinou A (2013) DNA structure-specific priming of ATR activation by DNA-PKcs. J Cell Biol 202: 421–429. doi: 10.1083/jcb.201304139. pmid:23897887
[80]
Hicks JK, Chute CL, Paulsen MT, Ragland RL, Howlett NG, Gueranger Q, Glover TW, Canman CE (2010) Differential roles for DNA polymerases eta, zeta, and REV1 in lesion bypass of intrastrand versus interstrand DNA cross-links. Mol Cell Biol 30: 1217–1230. doi: 10.1128/MCB.00993-09. pmid:20028736
