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dc.contributor.authorLu, Men
dc.contributor.authorBoschetti, Cen
dc.contributor.authorTunnacliffe, Aen
dc.date.accessioned2017-06-22T08:54:13Z
dc.date.available2017-06-22T08:54:13Z
dc.date.issued2015-11-13en
dc.identifier.urihttp://hdl.handle.net/10026.1/9514
dc.description.abstract

Juxtanuclear aggresomes form in cells when levels of aggregation-prone proteins exceed the capacity of the proteasome to degrade them. It is widely believed that aggresomes have a protective function, sequestering potentially damaging aggregates until these can be removed by autophagy. However, most in-cell studies have been carried out over a few days at most, and there is little information on the long term effects of aggresomes. To examine these long term effects, we created inducible, single-copy cell lines that expressed aggregation-prone polyglutamine proteins over several months. We present evidence that, as perinuclear aggresomes accumulate, they are associated with abnormal nuclear morphology and DNA double-strand breaks, resulting in cell cycle arrest via the phosphorylated p53 (Ser-15)-dependent pathway. Further analysis reveals that aggresomes can have a detrimental effect on mitosis by steric interference with chromosome alignment, centrosome positioning, and spindle formation. The incidence of apoptosis also increased in aggresome-containing cells. These severe defects developed gradually after juxtanuclear aggresome formation and were not associated with small cytoplasmic aggregates alone. Thus, our findings demonstrate that, in dividing cells, aggresomes are detrimental over the long term, rather than protective. This suggests a novel mechanism for polyglutamine-associated developmental and cell biological abnormalities, particularly those with early onset and non-neuronal pathologies.

en
dc.format.extent27986 - 28000en
dc.languageengen
dc.language.isoengen
dc.subjectDNA damageen
dc.subjectHuntington diseaseen
dc.subjectaggresomeen
dc.subjectapoptosisen
dc.subjectcell cycle arresten
dc.subjectmitotic defectsen
dc.subjectp53en
dc.subjectpolyglutamineen
dc.subjectprotein aggregationen
dc.subjectAutophagyen
dc.subjectCell Cycle Checkpointsen
dc.subjectCell Lineen
dc.subjectCell Nucleusen
dc.subjectDNA Breaks, Double-Strandeden
dc.subjectHumansen
dc.subjectInclusion Bodiesen
dc.subjectMitosisen
dc.subjectPeptidesen
dc.subjectPhosphorylationen
dc.subjectProteasome Endopeptidase Complexen
dc.subjectProtein Foldingen
dc.subjectSpindle Apparatusen
dc.subjectTumor Suppressor Protein p53en
dc.titleLong Term Aggresome Accumulation Leads to DNA Damage, p53-dependent Cell Cycle Arrest, and Steric Interference in Mitosis.en
dc.typeJournal Article
plymouth.author-urlhttps://www.ncbi.nlm.nih.gov/pubmed/26408200en
plymouth.issue46en
plymouth.volume290en
plymouth.publication-statusPublisheden
plymouth.journalJ Biol Chemen
dc.identifier.doi10.1074/jbc.M115.676437en
plymouth.organisational-group/Plymouth
plymouth.organisational-group/Plymouth/00 Groups by role
plymouth.organisational-group/Plymouth/00 Groups by role/Academics
plymouth.organisational-group/Plymouth/Faculty of Science and Engineering
plymouth.organisational-group/Plymouth/Faculty of Science and Engineering/School of Biological and Marine Sciences
plymouth.organisational-group/Plymouth/REF 2021 Researchers by UoA
plymouth.organisational-group/Plymouth/REF 2021 Researchers by UoA/UoA07 Earth Systems and Environmental Sciences
dc.publisher.placeUnited Statesen
dc.identifier.eissn1083-351Xen
dc.rights.embargoperiod12 monthsen
rioxxterms.versionofrecord10.1074/jbc.M115.676437en
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/under-embargo-all-rights-reserveden
rioxxterms.typeJournal Article/Reviewen


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