Small-molecule inhibition of aging-associated chromosomal instability delays cellular senescence.
EMBO Rep
; 21(5): e49248, 2020 05 06.
Article
em En
| MEDLINE
| ID: mdl-32134180
ABSTRACT
Chromosomal instability (CIN) refers to the rate at which cells are unable to properly segregate whole chromosomes, leading to aneuploidy. Besides its prevalence in cancer cells and postulated implications in promoting tumorigenesis, studies in aneuploidy-prone mouse models uncovered an unanticipated link between CIN and aging. Using young to old-aged human dermal fibroblasts, we observed a dysfunction of the mitotic machinery arising with age that mildly perturbs chromosome segregation fidelity and contributes to the generation of fully senescent cells. Here, we investigated mitotic mechanisms that contribute to age-associated CIN. We found that elderly cells have an increased number of stable kinetochore-microtubule (k-MT) attachments and decreased efficiency in the correction of improper k-MT interactions. Chromosome mis-segregation rates in old-aged cells decreased upon both genetic and small-molecule enhancement of MT-depolymerizing kinesin-13 activity. Notably, restored chromosome segregation accuracy inhibited the phenotypes of cellular senescence. Therefore, we provide mechanistic insight into age-associated CIN and disclose a strategy for the use of a small-molecule to inhibit age-associated CIN and to delay the cellular hallmarks of aging.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Segregação de Cromossomos
/
Instabilidade Cromossômica
Tipo de estudo:
Risk_factors_studies
Limite:
Humans
Idioma:
En
Revista:
EMBO Rep
Assunto da revista:
BIOLOGIA MOLECULAR
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
Portugal