The DNA damage response induces inflammation and senescence by inhibiting autophagy of GATA4

Abstract

Cellular senescence is a terminal stress-activated program controlled by the p53 and p16INK4a tumor suppressor proteins. A striking feature of senescence is the senescence-associated secretory phenotype (SASP), a pro-inflammatory response linked to tumor promotion and aging. We have identified the transcription factor GATA4 as a senescence and SASP regulator. GATA4 is stabilized in cells undergoing senescence and is required for the SASP. Normally, GATA4 is degraded by p62-mediated selective autophagy, but this regulation is suppressed during senescence, thereby stabilizing GATA4. GATA4 in turn activates the transcription factor NF-κB to initiate the SASP and facilitate senescence. GATA4 activation depends on the DNA damage response regulators ATM and ATR, but not on p53 or p16INK4a. GATA4 accumulates in multiple tissues, including the aging brain, and could contribute to aging and its associated inflammation.

Postinfarction Hearts Are Protected by Premature Senescent Cardiomyocytes Via GATA4‐Dependent CCN1 Secretion

“…GATA4 was identified as the key mediator of SASP, which was activated by damaged DNA and able to influence multiple tissue‐remodeling in a context‐dependent manner 12. In this study, we observed increased cardiomyocytes with damaged DNA based on γ‐H2AX immunostaining in postinfarction hearts (Figure 2A).…”

“…Masson staining and dual immunofluorescence staining were included to establish that cardiomyocytes underwent senescence after hypoxia. Regarding its functional role, SASP was important for senescence to participate in tissue remodeling that was maintained by transcription factor GATA4 12. In this study, we noticed an increase of GATA4 accumulation in the border zones, where the senescence markers are also highly expressed.…”

“…Upon DNA damage response, GATA4 is activated and in turn, initiates the secretion of inflammation factors by activating transcription factor NF‐kB 12. Furthermore, it was verified that GATA4‐mediated senescence and secretory phenotype are involved in multiple aging tissues including brain, skin, and liver 12. In this study, we investigated whether cardiomyocyte senescence participated in post‐AMI heart remodeling and whether the underlying mechanism is related to GATA4.…”

“…Mechanically, senescent cells can affect surrounding cells and play active roles in tissue remodeling by secreting such proteins as proinflammatory cytokines, chemokines, and growth factors (senescence‐associated secretory phenotype, SASP) 11. GATA‐binding factor 4 (GATA4) is required to maintain senescence and SASP 12. Upon DNA damage response, GATA4 is activated and in turn, initiates the secretion of inflammation factors by activating transcription factor NF‐kB 12.…”

“…GATA‐binding factor 4 (GATA4) is required to maintain senescence and SASP 12. Upon DNA damage response, GATA4 is activated and in turn, initiates the secretion of inflammation factors by activating transcription factor NF‐kB 12. Furthermore, it was verified that GATA4‐mediated senescence and secretory phenotype are involved in multiple aging tissues including brain, skin, and liver 12.…”