Abstract
Senescent cells, damaged cells that permanently exit the cell cycle, play important roles in development, tissue homeostasis, and tumorigenesis. Although many of these roles are beneficial in acute responses to stress and damage, the persistent accumulation of senescent cells is associated with many chronic diseases through their proinflammatory senescence-associated secretory phenotype (SASP). SASP expression is linked to DNA damage; however, the mechanisms that control the SASP are incompletely understood. More recently, it has been shown that senescent cells shed fragments of nuclear chromatin into the cytoplasm, so called cytoplasmic chromatin fragments (CCF). Here, we provide an overview of the current evidence linking DNA damage to the SASP through the formation of CCF. We describe mechanisms of CCF generation and their functional role in senescent cells, with emphasis on therapeutic potential.
Highlights
Cellular senescence, a stable cell cycle arrest, is considered a hallmark of aging and contributes to aging-associated diseases (Herranz and Gil, 2018)
The pro-aging feature of senescence is in part mediated by the secretion of a large array of proinflammatory factors, termed the senescence-associated secretory phenotype (SASP), that leads to chronic inflammation, promoting tissue dysfunction and diseases (Rodier and Campisi, 2011)
We and others showed that SASP is mainly driven by the presence of cytoplasmic chromatin fragments (CCF), generated via a nuclear-cytoplasmic blebbing process (Dou et al, 2015; Dou et al, 2017; Gluck et al, 2017; Ivanov et al, 2013; Vizioli et al, 2020; Yang et al, 2017)
Summary
A stable cell cycle arrest, is considered a hallmark of aging and contributes to aging-associated diseases (Herranz and Gil, 2018). Accumulation of DNA in the cytoplasm serves as a potent danger signal that activates the innate immunity cytosolic DNA sensing cyclic GMP–AMP synthase (cGAS)-STING pathway, leading to proinflammatory responses (De Cecco et al, 2019; Dou et al, 2017; Gluck et al, 2017; Harding et al, 2017; Mackenzie et al, 2017; Simon et al, 2019; West and Shadel, 2017; Yang et al, 2017).
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