1. Long Term Aggresome Accumulation Leads to DNA Damage, p53-dependent Cell Cycle Arrest, and Steric Interference in Mitosis
- Author
-
Chiara Boschetti, Meng Lu, and Alan Tunnacliffe
- Subjects
Proteasome Endopeptidase Complex ,Protein Folding ,Cell cycle checkpoint ,DNA damage ,education ,Mitosis ,Spindle Apparatus ,Biology ,Biochemistry ,Cell Line ,03 medical and health sciences ,0302 clinical medicine ,Autophagy ,medicine ,Humans ,DNA Breaks, Double-Stranded ,Phosphorylation ,Molecular Biology ,030304 developmental biology ,Cell Nucleus ,Inclusion Bodies ,0303 health sciences ,Cell Cycle Checkpoints ,Cell Biology ,Cell biology ,Spindle apparatus ,Cell nucleus ,Aggresome ,medicine.anatomical_structure ,Proteasome ,Tumor Suppressor Protein p53 ,Peptides ,Multipolar spindles ,030217 neurology & neurosurgery - 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.
- Published
- 2015