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

eLife

Ryan Kelly¹  Matt Kaeberlein²  Adam E Russell³  Jared Almazan³  Mung Gi Hong³  Kenneth L Chen³  Matthew M Crane³  Bao Nguyen³  Joslyn E Goings³  Ben W Blue³  Riley Whalen³  Brent J Schafer³ 

[1] Department of Genome Sciences, University of Washington, Seattle, United States;Medical Scientist Training Program, University of Washington, Seattle, United States;Department of Pathology, University of Washington, Seattle, United States;

关键词: aging;    replicative lifespan;    senescence;    extrachromosomal rDNA circles;    microfluidics;    histones;   

DOI  :  10.7554/eLife.50778

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown