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dc.contributor.authorGil-Ranedo, J
dc.contributor.authorHernando, E
dc.contributor.authorRiolobos, L
dc.contributor.authorDomínguez, C
dc.contributor.authorKann, M
dc.contributor.authorAlmendral, JM
dc.contributor.editorSamulski RJ
dc.date.accessioned2015-08-17T11:39:08Z
dc.date.available2015-08-17T11:39:08Z
dc.date.issued2015
dc.identifier.issn1553-7366
dc.identifier.issn1553-7374
dc.identifier.otherARTN e1004920
dc.identifier.urihttp://hdl.handle.net/10026.1/3522
dc.description.abstract

It is unknown whether the mammalian cell cycle could impact the assembly of viruses maturing in the nucleus. We addressed this question using MVM, a reference member of the icosahedral ssDNA nuclear parvoviruses, which requires cell proliferation to infect by mechanisms partly understood. Constitutively expressed MVM capsid subunits (VPs) accumulated in the cytoplasm of mouse and human fibroblasts synchronized at G0, G1, and G1/S transition. Upon arrest release, VPs translocated to the nucleus as cells entered S phase, at efficiencies relying on cell origin and arrest method, and immediately assembled into capsids. In synchronously infected cells, the consecutive virus life cycle steps (gene expression, proteins nuclear translocation, capsid assembly, genome replication and encapsidation) proceeded tightly coupled to cell cycle progression from G0/G1 through S into G2 phase. However, a DNA synthesis stress caused by thymidine irreversibly disrupted virus life cycle, as VPs became increasingly retained in the cytoplasm hours post-stress, forming empty capsids in mouse fibroblasts, thereby impairing encapsidation of the nuclear viral DNA replicative intermediates. Synchronously infected cells subjected to density-arrest signals while traversing early S phase also blocked VPs transport, resulting in a similar misplaced cytoplasmic capsid assembly in mouse fibroblasts. In contrast, thymidine and density arrest signals deregulating virus assembly neither perturbed nuclear translocation of the NS1 protein nor viral genome replication occurring under S/G2 cycle arrest. An underlying mechanism of cell cycle control was identified in the nuclear translocation of phosphorylated VPs trimeric assembly intermediates, which accessed a non-conserved route distinct from the importin α2/β1 and transportin pathways. The exquisite cell cycle-dependence of parvovirus nuclear capsid assembly conforms a novel paradigm of time and functional coupling between cellular and virus life cycles. This junction may determine the characteristic parvovirus tropism for proliferative and cancer cells, and its disturbance could critically contribute to persistence in host tissues.

dc.format.extente1004920-e1004920
dc.format.mediumElectronic-eCollection
dc.languageen
dc.language.isoeng
dc.publisherPublic Library of Science (PLoS)
dc.subjectAnimals
dc.subjectCapsid
dc.subjectCapsid Proteins
dc.subjectCell Cycle
dc.subjectCell Line
dc.subjectCell Nucleus
dc.subjectFibroblasts
dc.subjectFlow Cytometry
dc.subjectFluorescent Antibody Technique
dc.subjectHost-Parasite Interactions
dc.subjectHumans
dc.subjectMice
dc.subjectMinute Virus of Mice
dc.subjectParvoviridae Infections
dc.subjectVirus Assembly
dc.titleThe Mammalian Cell Cycle Regulates Parvovirus Nuclear Capsid Assembly
dc.typejournal-article
dc.typeArticle
plymouth.author-urlhttps://www.ncbi.nlm.nih.gov/pubmed/26067441
plymouth.issue6
plymouth.volume11
plymouth.publisher-urlhttp://dx.doi.org/10.1371/journal.ppat.1004920
plymouth.publication-statusPublished online
plymouth.journalPLOS Pathogens
dc.identifier.doi10.1371/journal.ppat.1004920
plymouth.organisational-group/Plymouth
plymouth.organisational-group/Plymouth/Faculty of Health
plymouth.organisational-group/Plymouth/Faculty of Health/Peninsula Medical School
plymouth.organisational-group/Plymouth/REF 2021 Researchers by UoA
plymouth.organisational-group/Plymouth/REF 2021 Researchers by UoA/UoA01 Clinical Medicine
plymouth.organisational-group/Plymouth/Users by role
plymouth.organisational-group/Plymouth/Users by role/Academics
dc.publisher.placeUnited States
dcterms.dateAccepted2015-04-28
dc.identifier.eissn1553-7374
dc.rights.embargoperiodNot known
rioxxterms.versionofrecord10.1371/journal.ppat.1004920
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2015-06
rioxxterms.typeJournal Article/Review


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