title: Long Term Aggresome Accumulation Leads to DNA Damage, p53-dependent Cell Cycle Arrest, and Steric Interference in Mitosis.
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.
authors.affiliation: From the Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge, CB2 3RA, United Kingdom.
authors.forename: Meng
authors.initials: M
authors.lastname: Lu
authors.affiliation: From the Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge, CB2 3RA, United Kingdom.
authors.forename: Chiara
authors.initials: C
authors.lastname: Boschetti
authors.affiliation: From the Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge, CB2 3RA, United Kingdom at10004@cam.ac.uk.
authors.forename: Alan
authors.initials: A
authors.lastname: Tunnacliffe
mesh_terms: D001343:Autophagy; D059447:Cell Cycle Checkpoints; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism / Q000648:ultrastructure; D053903:DNA Breaks, Double-Stranded; D006801:Humans; D002479:Inclusion Bodies / Q000737:chemistry / Q000378:metabolism*; D008938:Mitosis; D010455:Peptides / Q000737:chemistry / Q000378:metabolism*; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D017510:Protein Folding; D008941:Spindle Apparatus / Q000378:metabolism* / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D010455:Peptides; D016159:Tumor Suppressor Protein p53; C097188:polyglutamine; D046988:Proteasome Endopeptidase Complex
keywords: DNA damage; Huntington disease; aggresome; apoptosis; cell cycle arrest; mitotic defects; p53; polyglutamine; protein aggregation