Downregulation of cytoplasmic DNases is implicated in cytoplasmic DNA accumulation and SASP in senescent cells

Abstract

Accumulating evidence indicates that the senescence-associated secretory phenotype (SASP) contributes to many aspects of physiology and disease. Thus, controlling the SASP will have tremendous impacts on our health. However, our understanding of SASP regulation is far from complete. Here, we show that cytoplasmic accumulation of nuclear DNA plays key roles in the onset of SASP. Although both DNase2 and TREX1 rapidly remove the cytoplasmic DNA fragments emanating from the nucleus in pre-senescent cells, the expression of these DNases is downregulated in senescent cells, resulting in the cytoplasmic accumulation of nuclear DNA. This causes the aberrant activation of cGAS-STING cytoplasmic DNA sensors, provoking SASP through induction of interferon-β. Notably, the blockage of this pathway prevents SASP in senescent hepatic stellate cells, accompanied by a decline of obesity-associated hepatocellular carcinoma development in mice. These findings provide valuable new insights into the roles and mechanisms of SASP and possibilities for their control.

Senescent cells: Living or dying is a matter of NK cells

“…Recent studies highlight the link between cytosolic DNA sensing and the induction of cellular senescence, stressing the pivotal role of the cGAS‐STING pathway, thus, providing the molecular basis for considering cellular senescence as a defense system against virus infection, as well as genomic/neoplastic insult . Accordingly, type I IFNs result protective against retrotransposition events and cells accumulating DNA damage produce endogenous IFN‐β and become senescent .…”

“…83 Recent studies highlight the link between cytosolic DNA sensing and the induction of cellular senescence, stressing the pivotal role of the cGAS-STING pathway, thus, providing the molecular basis for considering cellular senescence as a defense system against virus infection, as well as genomic/neoplastic insult. [84][85][86][87] Accordingly, type I IFNs result protective against retrotransposition events 88 and cells accumulating DNA damage produce endogenous IFN-and become senescent. 89,90 Hence, it is reasonable that type I IFN signaling drives cellular response upon both virus infection and DNA damage to protect genome integrity, becoming actually a tumor suppressive mechanism.…”

Post‐transcriptional control of immune responses and its potential application

“…As mentioned above, IFN‐β production is reported to be regulated by m 6 A deposition. Since the role of IFN‐β upon dsDNA stimulation is implicated in cellular senescence as well as pathogen control, the regulation of m 6 A status may have an impact on not only infection but also aging …”

“…Since the role of IFN-b upon dsDNA stimulation is implicated in cellular senescence as well as pathogen control, the regulation of m 6 A status may have an impact on not only infection but also aging. 80 Although these compounds could be used for modulating above-mentioned biological processes, they are relatively nonspecific, inherently inhibiting many other hydroxylases that require a-KG. To circumvent this, several attempts to find demethylase-specific inhibitors have been reported.…”

Cellular senescence and senescence‐associated T cells as a potential therapeutic target

“…In addition, senescent cells promote various inflammatory processes and carcinogenesis by the secretion of inflammatory cytokines, chemokines and matrix metalloproteases. 11 Importantly, the expression levels of DNases are decreased in senescent cells, resulting in the cytoplasmic accumulation of nuclear DNA, which leads to the activation of cytoplasmic DNA sensors, provoking the SASP through the induction of interferon-β. 10 Very recently, Hara et al showed that the cytoplasmic accumulation of nuclear DNA plays key roles in the onset of SASP.…”