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

TLDR

Cellular senescence is a terminal stress‑activated program governed by p53 and p16(INK4a) and is marked by a senescence‑associated secretory phenotype that promotes inflammation, tumor progression, and aging. In senescent cells, p62‑mediated selective autophagy of GATA4 is suppressed, stabilizing the transcription factor, which then requires ATM and ATR but not p53 or p16(INK4a) for activation. GATA4 is essential for senescence and SASP, activates NF‑κB, and its accumulation in tissues such as the aging brain indicates a potential contribution to age‑related inflammation.

Abstract

Cellular senescence is a terminal stress-activated program controlled by the p53 and p16(INK4a) 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 p16(INK4a). GATA4 accumulates in multiple tissues, including the aging brain, and could contribute to aging and its associated inflammation.