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2017 ; 114
(23
): E4612-E4620
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cGAS is essential for cellular senescence
#MMPMID28533362
Yang H
; Wang H
; Ren J
; Chen Q
; Chen ZJ
Proc Natl Acad Sci U S A
2017[Jun]; 114
(23
): E4612-E4620
PMID28533362
show ga
Cellular senescence is a natural barrier to tumorigenesis and it contributes to
the antitumor effects of several therapies, including radiation and
chemotherapeutic drugs. Senescence also plays an important role in aging,
fibrosis, and tissue repair. The DNA damage response is a key event leading to
senescence, which is characterized by the senescence-associated secretory
phenotype (SASP) that includes expression of inflammatory cytokines. Here we show
that cGMP-AMP (cGAMP) synthase (cGAS), a cytosolic DNA sensor that activates
innate immunity, is essential for senescence. Deletion of cGAS accelerated the
spontaneous immortalization of mouse embryonic fibroblasts. cGAS deletion also
abrogated SASP induced by spontaneous immortalization or DNA damaging agents,
including radiation and etoposide. cGAS is localized in the cytoplasm of
nondividing cells but enters the nucleus and associates with chromatin DNA during
mitosis in proliferating cells. DNA damage leads to accumulation of damaged DNA
in cytoplasmic foci that contain cGAS. In human lung adenocarcinoma patients, low
expression of cGAS is correlated with poor survival. These results indicate that
cGAS mediates cellular senescence and retards immortalization. This is distinct
from, and complementary to, the role of cGAS in activating antitumor immunity.
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