Cited by 51Virus-based gene therapy researchHIV Research and TreatmentHIV/AIDS drug development and treatment

Structural basis for spumavirus GAG tethering to chromatin

Open access
Lesbats, Paul, Serrao, Erik, Maskell, Daniel P., Pye, Valerie E., O’Reilly, Nicola, Lindemann, Dirk, Engelman, Alan N., Cherepanov, Peter·2017·Proceedings of the National Academy of Sciences

Abstract

Significance: Spumaviruses are being developed as vectors for gene-therapy applications, but how these retroviruses select genomic locations for integration remains unknown. Here we use X-ray crystallography to visualize the interaction between the spumaviral GAG protein and a nucleosome. We show that this interaction is essential for the observed distribution of spumavirus integration sites in various human cell types. Thus, despite stark differences in the mechanistic details of spumavirus and orthoretrovirus replication strategies, both retroviral subfamilies depend on their structural proteins to locate optimal integration sites.

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Crossref · 10.1073/pnas.1621159114

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  • The R540Q substitution in PFV Gag decouples chromatin binding sequence-nucleosome binding in vitro and redirects a large portion of PFV integration events into centromeres.

    “The R540Q substitution in PFV Gag, which altered an Arg residue conserved across this group of H2A/H2B binding proteins, decoupled CBS-nucleosome binding in vitro and redirected a large portion of PFV integration events into centromeres92.”

    From Structure and function of retroviral integrase (2022) · cites this paper as [92]

  • The PFV Gag chromatin binding sequence binds nucleosomes via an acidic patch predominantly composed of core histone H2A/H2B heterodimers.

    “The PFV Gag CBS binds nucleosomes via an acidic patch predominantly composed of core histone H2A/H2B heterodimers91,92”

    From Structure and function of retroviral integrase (2022) · cites this paper as [92]

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Authors
Lesbats, P., Serrao, E., Maskell, D. P., Pye, V. E., O’Reilly, N., Lindemann, D., Engelman, A. N., & Cherepanov, P.
Affiliations
  • The Francis Crick Institute (GB)
  • Harvard University (US)
  • Technische Universität Dresden (DE)
Venue
Proceedings of the National Academy of Sciences
Published
2017-05-10
Volume
114
Issue
21
Pages
5509-5514
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
OpenAlex
W2613642509
Cited by
51
References
59
Citations by year
2026: 1 · 2025: 3 · 2024: 5 · 2023: 7 · 2022: 6 · 2021: 7 · 2020: 8 · 2019: 8 · 2018: 5 · 2016: 1
FWCI
3.80
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
  • Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
  • HAL (submittedVersion, other-oa)
  • Figshare (submittedVersion, cc-by)
  • Oskar-Bordeaux (Universite de Bordeaux) (submittedVersion)
  • Spiral (Imperial College London) (submittedVersion, other-oa)
Funders
  • HHS | NIH | National Institute of General Medical Sciences (GM082251)
  • HHS | NIH | National Institute of Allergy and Infectious Diseases (AI039394, AI060354)
  • Deutsche Forschungsgemeinschaft (LI 621/10-1, LI 621/11-1)
  • Cancer Research UK (FC001061)
  • Wellcome Trust (FC001061)
  • Medical Research Council (FC001061)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
  • Life Sciences › Immunology and Microbiology › Virology › HIV Research and Treatment
  • Health Sciences › Medicine › Infectious Diseases › HIV/AIDS drug development and treatment
Keywords
Gag protein, nucleosome, chromatin tethering, gene therapy vectors, retroviral integration
MeSH terms
Histones, Nucleosomes, Spumavirus, Virus Integration

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