Evidence for DNA Hairpin Recognition by Zta at the Epstein-Barr Virus Origin of Lytic Replication

Overview

Journal J Virol

Publisher American Society for Microbiology

Date 2010 May 7

PMID 20444899

Citations 9

Authors

Andrew J Rennekamp

Pu Wang

Paul M Lieberman

Affiliations

Soon will be listed here.

Abstract

The Epstein-Barr virus immediate-early protein (Zta) plays an essential role in viral lytic activation and pathogenesis. Zta is a basic zipper (b-Zip) domain-containing protein that binds multiple sites in the viral origin of lytic replication (OriLyt) and is required for lytic-cycle DNA replication. We present evidence that Zta binds to a sequence-specific, imperfect DNA hairpin formed by an inverted repeat within the upstream essential element (UEE) of OriLyt. Mutations in the OriLyt sequence that are predicted to disrupt hairpin formation also disrupt Zta binding in vitro. Restoration of the hairpin rescues the defect. We also show that OriLyt DNA isolated from replicating cells contains a nuclease-sensitive region that overlaps with the inverted-repeat region of the UEE. Furthermore, point mutations in Zta that disrupt specific recognition of the UEE hairpin are defective for activation of lytic replication. These data suggest that Zta acts by inducing and/or stabilizing a DNA hairpin structure during productive infection. The DNA hairpin at OriLyt with which Zta interacts resembles DNA structures formed at other herpesvirus origins and may therefore represent a common secondary structure used by all herpesvirus family members during the initiation of DNA replication.

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References

Francis A, Gradoville L, Miller G . Alteration of a single serine in the basic domain of the Epstein-Barr virus ZEBRA protein separates its functions of transcriptional activation and disruption of latency. J Virol. 1997; 71(4):3054-61. PMC: 191435. DOI: 10.1128/JVI.71.4.3054-3061.1997. View

Koff A, Schwedes J, Tegtmeyer P . Herpes simplex virus origin-binding protein (UL9) loops and distorts the viral replication origin. J Virol. 1991; 65(6):3284-92. PMC: 240986. DOI: 10.1128/JVI.65.6.3284-3292.1991. View

Marintcheva B, Weller S . Helicase motif Ia is involved in single-strand DNA-binding and helicase activities of the herpes simplex virus type 1 origin-binding protein, UL9. J Virol. 2003; 77(4):2477-88. PMC: 141079. DOI: 10.1128/jvi.77.4.2477-2488.2003. View

Hong G, Kumar P, Wang L, Damania B, Gulley M, Delecluse H . Epstein-Barr virus lytic infection is required for efficient production of the angiogenesis factor vascular endothelial growth factor in lymphoblastoid cell lines. J Virol. 2005; 79(22):13984-92. PMC: 1280197. DOI: 10.1128/JVI.79.22.13984-13992.2005. View

Aslani A, Macao B, Simonsson S, Elias P . Complementary intrastrand base pairing during initiation of Herpes simplex virus type 1 DNA replication. Proc Natl Acad Sci U S A. 2001; 98(13):7194-9. PMC: 34645. DOI: 10.1073/pnas.121177198. View

Liptak L, Uprichard S, Knipe D . Functional order of assembly of herpes simplex virus DNA replication proteins into prereplicative site structures. J Virol. 1996; 70(3):1759-67. PMC: 190001. DOI: 10.1128/JVI.70.3.1759-1767.1996. View

Sarisky R, Hayward G . Evidence that the UL84 gene product of human cytomegalovirus is essential for promoting oriLyt-dependent DNA replication and formation of replication compartments in cotransfection assays. J Virol. 1996; 70(11):7398-413. PMC: 190807. DOI: 10.1128/JVI.70.11.7398-7413.1996. View

Jenson H, Miller G . Polymorphisms of the region of the Epstein-Barr virus genome which disrupts latency. Virology. 1988; 165(2):549-64. DOI: 10.1016/0042-6822(88)90599-5. View

Wang P, Day L, Dheekollu J, Lieberman P . A redox-sensitive cysteine in Zta is required for Epstein-Barr virus lytic cycle DNA replication. J Virol. 2005; 79(21):13298-309. PMC: 1262569. DOI: 10.1128/JVI.79.21.13298-13309.2005. View

10.

He X, Lehman I . Unwinding of a herpes simplex virus type 1 origin of replication (Ori(S)) by a complex of the viral origin binding protein and the single-stranded DNA binding protein. J Virol. 2000; 74(12):5726-8. PMC: 112062. DOI: 10.1128/jvi.74.12.5726-5728.2000. View

11.

Wang P, Rennekamp A, Yuan Y, Lieberman P . Topoisomerase I and RecQL1 function in Epstein-Barr virus lytic reactivation. J Virol. 2009; 83(16):8090-8. PMC: 2715768. DOI: 10.1128/JVI.02379-08. View

12.

AuCoin D, Colletti K, Xu Y, Cei S, Pari G . Kaposi's sarcoma-associated herpesvirus (human herpesvirus 8) contains two functional lytic origins of DNA replication. J Virol. 2002; 76(15):7890-6. PMC: 136389. DOI: 10.1128/jvi.76.15.7890-7896.2002. View

13.

Zhang Q, Hong Y, Dorsky D, Holley-Guthrie E, Zalani S, Elshiekh N . Functional and physical interactions between the Epstein-Barr virus (EBV) proteins BZLF1 and BMRF1: Effects on EBV transcription and lytic replication. J Virol. 1996; 70(8):5131-42. PMC: 190468. DOI: 10.1128/JVI.70.8.5131-5142.1996. View

14.

Schepers A, Pich D, Hammerschmidt W . A transcription factor with homology to the AP-1 family links RNA transcription and DNA replication in the lytic cycle of Epstein-Barr virus. EMBO J. 1993; 12(10):3921-9. PMC: 413675. DOI: 10.1002/j.1460-2075.1993.tb06070.x. View

15.

Boehmer P, Lehman I . Herpes simplex virus DNA replication. Annu Rev Biochem. 1997; 66:347-84. DOI: 10.1146/annurev.biochem.66.1.347. View

16.

Gustafsson C, Hammarsten O, Falkenberg M, Elias P . Herpes simplex virus DNA replication: a spacer sequence directs the ATP-dependent formation of a nucleoprotein complex at oriS. Proc Natl Acad Sci U S A. 1994; 91(11):4629-33. PMC: 43841. DOI: 10.1073/pnas.91.11.4629. View

17.

Liao G, Wu F, Hayward S . Interaction with the Epstein-Barr virus helicase targets Zta to DNA replication compartments. J Virol. 2001; 75(18):8792-802. PMC: 115124. DOI: 10.1128/jvi.75.18.8792-8802.2001. View

18.

Miller G, El-Guindy A, Countryman J, Ye J, Gradoville L . Lytic cycle switches of oncogenic human gammaherpesviruses. Adv Cancer Res. 2007; 97:81-109. DOI: 10.1016/S0065-230X(06)97004-3. View

19.

Lee S, Lehman I . Unwinding of the box I element of a herpes simplex virus type 1 origin by a complex of the viral origin binding protein, single-strand DNA binding protein, and single-stranded DNA. Proc Natl Acad Sci U S A. 1997; 94(7):2838-42. PMC: 20283. DOI: 10.1073/pnas.94.7.2838. View

20.

Falkenberg M, Lehman I, Elias P . Leading and lagging strand DNA synthesis in vitro by a reconstituted herpes simplex virus type 1 replisome. Proc Natl Acad Sci U S A. 2000; 97(8):3896-900. PMC: 18113. DOI: 10.1073/pnas.97.8.3896. View