Acetylation of E2 by P300 Mediates Topoisomerase Entry at the Papillomavirus Replicon

Yanique Thomas, Elliot Androphy

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Human papillomavirus (HPV) E2 proteins are integral for the transcription of viral genes and the replication and maintenance of viral genomes in host cells. E2 recruits the viral DNA helicase E1 to the origin. A lysine (K111), highly conserved among almost all papillomavirus (PV) E2 proteins, is a target for P300 (EP300) acetylation and is critical for viral DNA replication (E. J. Quinlan, S. P. Culleton, S. Y. Wu, C. M. Chiang, et al., J Virol 87:1497-1507, 2013, https://doi.org/10.1128/JVI.02771-12; Y. Thomas and E. J. Androphy, J Virol 92:e01912-17, 2018, https://doi.org/10.1128/JVI.01912-17). Since the viral genome exists as a covalently closed circle of double-stranded DNA, topoisomerase 1 (Topo1) is thought to be required for progression of the replication forks. Due to the specific effect of K111 mutations on DNA unwinding (Y. Thomas and E. J. Androphy, J Virol 92:e01912-17, 2018, https://doi.org/10.1128/JVI.01912-17), we demonstrate that the E2 protein targets Topo1 to the viral origin, and this depends on acetylation of K111. The effect was corroborated by functional replication assays, in which higher levels of P300, but not its homolog CBP, caused enhanced replication with wild-type E2 but not the acetylation-defective K111 arginine mutant. These data reveal a novel role for lysine acetylation during viral DNA replication by regulating topoisomerase recruitment to the replication origin.IMPORTANCE Human papillomaviruses affect an estimated 75% of the sexually active adult population in the United States, with 5.5 million new cases emerging every year. More than 200 HPV genotypes have been identified; a subset of them are linked to the development of cancers from these epithelial infections. Specific antiviral medical treatments for infected individuals are not available. This project examines the mechanisms that control viral genome replication and may allow the development of novel therapeutics.

Original languageEnglish (US)
JournalJournal of virology
Volume93
Issue number7
DOIs
StatePublished - Apr 1 2019

Fingerprint

replicon
Replicon
Papillomaviridae
acetylation
Acetylation
Viral Genome
Viral DNA
DNA replication
DNA Replication
Lysine
genome
lysine
DNA helicases
DNA Helicases
DNA topoisomerase
replication origin
Type I DNA Topoisomerase
Replication Origin
Viral Genes
proteins

Keywords

  • DNA replication
  • E2
  • P300
  • papillomavirus
  • topoisomerase 1

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

Cite this

Acetylation of E2 by P300 Mediates Topoisomerase Entry at the Papillomavirus Replicon. / Thomas, Yanique; Androphy, Elliot.

In: Journal of virology, Vol. 93, No. 7, 01.04.2019.

Research output: Contribution to journalArticle

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abstract = "Human papillomavirus (HPV) E2 proteins are integral for the transcription of viral genes and the replication and maintenance of viral genomes in host cells. E2 recruits the viral DNA helicase E1 to the origin. A lysine (K111), highly conserved among almost all papillomavirus (PV) E2 proteins, is a target for P300 (EP300) acetylation and is critical for viral DNA replication (E. J. Quinlan, S. P. Culleton, S. Y. Wu, C. M. Chiang, et al., J Virol 87:1497-1507, 2013, https://doi.org/10.1128/JVI.02771-12; Y. Thomas and E. J. Androphy, J Virol 92:e01912-17, 2018, https://doi.org/10.1128/JVI.01912-17). Since the viral genome exists as a covalently closed circle of double-stranded DNA, topoisomerase 1 (Topo1) is thought to be required for progression of the replication forks. Due to the specific effect of K111 mutations on DNA unwinding (Y. Thomas and E. J. Androphy, J Virol 92:e01912-17, 2018, https://doi.org/10.1128/JVI.01912-17), we demonstrate that the E2 protein targets Topo1 to the viral origin, and this depends on acetylation of K111. The effect was corroborated by functional replication assays, in which higher levels of P300, but not its homolog CBP, caused enhanced replication with wild-type E2 but not the acetylation-defective K111 arginine mutant. These data reveal a novel role for lysine acetylation during viral DNA replication by regulating topoisomerase recruitment to the replication origin.IMPORTANCE Human papillomaviruses affect an estimated 75{\%} of the sexually active adult population in the United States, with 5.5 million new cases emerging every year. More than 200 HPV genotypes have been identified; a subset of them are linked to the development of cancers from these epithelial infections. Specific antiviral medical treatments for infected individuals are not available. This project examines the mechanisms that control viral genome replication and may allow the development of novel therapeutics.",
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