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DNA damage checkpoint activation impairs chromatin homeostasis and promotes mitotic catastrophe during aging

Genome instability is a hallmark of aging and contributes to age-related disorders such as cancer and Alzheimer’s disease. The accumulation of DNA damage during aging has been linked to altered cell cycle dynamics and the failure of cell cycle checkpoints. Here, we use single cell imaging to study t...

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Detalles Bibliográficos
Autores principales: Crane, Matthew M, Russell, Adam E, Schafer, Brent J, Blue, Ben W, Whalen, Riley, Almazan, Jared, Hong, Mung Gi, Nguyen, Bao, Goings, Joslyn E, Chen, Kenneth L, Kelly, Ryan, Kaeberlein, Matt
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6850777/
https://www.ncbi.nlm.nih.gov/pubmed/31714209
http://dx.doi.org/10.7554/eLife.50778
Descripción
Sumario:Genome instability is a hallmark of aging and contributes to age-related disorders such as cancer and Alzheimer’s disease. The accumulation of DNA damage during aging has been linked to altered cell cycle dynamics and the failure of cell cycle checkpoints. Here, we use single cell imaging to study the consequences of increased genomic instability during aging in budding yeast and identify striking age-associated genome missegregation events. This breakdown in mitotic fidelity results from the age-related activation of the DNA damage checkpoint and the resulting degradation of histone proteins. Disrupting the ability of cells to degrade histones in response to DNA damage increases replicative lifespan and reduces genomic missegregations. We present several lines of evidence supporting a model of antagonistic pleiotropy in the DNA damage response where histone degradation, and limited histone transcription are beneficial to respond rapidly to damage but reduce lifespan and genomic stability in the long term.