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PMID: 26061770 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Structural basis for retroviral integration into nucleosomes.

Nature ·Vol. 523 ·No. 7560 ·2015-07-16 ·Pages 366-9

Maskell DP, Renault L, Serrao E, Lesbats P, Matadeen R, Hare S, Lindemann D, Engelman AN, Costa A, Cherepanov P

Abstract

Retroviral integration is catalysed by a tetramer of integrase (IN) assembled on viral DNA ends in a stable complex, known as the intasome. How the intasome interfaces with chromosomal DNA, which exists in the form of nucleosomal arrays, is currently unknown. Here we show that the prototype foamy virus (PFV) intasome is proficient at stable capture of nucleosomes as targets for integration. Single-particle cryo-electron microscopy reveals a multivalent intasome-nucleosome interface involving both gyres of nucleosomal DNA and one H2A-H2B heterodimer. While the histone octamer remains intact, the DNA is lifted from the surface of the H2A-H2B heterodimer to allow integration at strongly preferred superhelix location ±3.5 positions. Amino acid substitutions disrupting these contacts impinge on the ability of the intasome to engage nucleosomes in vitro and redistribute viral integration sites on the genomic scale. Our findings elucidate the molecular basis for nucleosome capture by the viral DNA recombination machinery and the underlying nucleosome plasticity that allows integration.

MeSH Terms
Amino Acid Substitution Binding Sites/genetics Cryoelectron Microscopy DNA/genetics,metabolism,ultrastructure Genome/genetics Histones/chemistry,metabolism,ultrastructure Integrases/metabolism Models, Molecular Nucleosomes/chemistry,genetics,ultrastructure,virology Protein Multimerization Recombination, Genetic Spumavirus/chemistry,genetics,metabolism,ultrastructure Virus Integration
Chemicals
Histones Nucleosomes DNA Integrases
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Maskell Daniel P
Chromatin Structure and Mobile DNA, The Francis Crick Institute, Blanche Lane, South Mimms EN6 3LD, UK.
Renault Ludovic
1] Architecture and Dynamics of Macromolecular Machines, Clare Hall Laboratories, The Francis Crick Institute, Blanche Lane, South Mimms EN6 3LD, UK [2] National Institute for Biological Standards and Control, Microscopy and Imaging, Blanche Lane, South Mimms EN6 3QG, UK.
Serrao Erik
Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, Massachusetts 02215, USA.
Lesbats Paul
Chromatin Structure and Mobile DNA, The Francis Crick Institute, Blanche Lane, South Mimms EN6 3LD, UK.
Matadeen Rishi
NeCEN, Gorlaeus Laboratory, Einsteinweg 55, Leiden, 2333, the Netherlands.
Hare Stephen
Division of Medicine, Imperial College London, St-Mary's Campus, Norfolk Place, London W2 1PG, UK.
Lindemann Dirk
Institute of Virology, Technische Universität Dresden, Fetscherstr. 74, Dresden 01307, Germany.
Engelman Alan N
Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, Massachusetts 02215, USA.
Costa Alessandro
Architecture and Dynamics of Macromolecular Machines, Clare Hall Laboratories, The Francis Crick Institute, Blanche Lane, South Mimms EN6 3LD, UK.
Cherepanov Peter
1] Chromatin Structure and Mobile DNA, The Francis Crick Institute, Blanche Lane, South Mimms EN6 3LD, UK [2] Division of Medicine, Imperial College London, St-Mary's Campus, Norfolk Place, London W2 1PG, UK.
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Article Info
Journal
Nature
Abbr.
Nature
ISSN
1476-4687
DOI
10.1038/nature14495
Published
2015-07-16
Epub
2015-00-10
Pages
366-9
Language
English
Region
England
NLM ID
0410462
PMCID
PMC4530500
Subset
IM
Grants
NIGMS NIH HHS · P50 GM082251 · United States
NIGMS NIH HHS · P50 GM082251-06 · United States
Cancer Research UK · 15272 · United Kingdom
NIAID NIH HHS · R01 AI070042-08 · United States
NIAID NIH HHS · R01 AI070042 · United States
Databases
GEO
GSE67730
External Links
PubMed source DOI: 10.1038/nature14495 PMC Full Text View journal details
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