TY - JOUR
T1 - ATR prevents Ca2+ overload-induced necrotic cell death through phosphorylation-mediated inactivation of PARP1 without DNA damage signaling
AU - Li, Zhengke
AU - Wang-Heaton, Hui
AU - Cartwright, Brian M.
AU - Makinwa, Yetunde
AU - Hilton, Benjamin A.
AU - Musich, Phillip R.
AU - Shkriabai, Nikolozi
AU - Kvaratskhelia, Mamuka
AU - Guan, Shengheng
AU - Chen, Qian
AU - Yu, Xiaochun
AU - Zou, Yue
N1 - Publisher Copyright:
© 2021 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.
PY - 2021/5
Y1 - 2021/5
N2 - Hyperactivation of PARP1 is known to be a major cause of necrotic cell death by depleting NAD+/ATP pools during Ca2+ overload which is associated with many ischemic diseases. However, little is known about how PARP1 hyperactivity is regulated during calcium overload. In this study we show that ATR kinase, well known for its role in DNA damage responses, suppresses ionomycin, glutamate, or quinolinic acid-induced necrotic death of cells including SH-SY5Y neuronal cells. We found that the inhibition of necrosis requires the kinase activity of ATR. Specifically, ATR binds to and phosphorylates PARP1 at Ser179 after the ionophore treatments. This site-specific phosphorylation inactivates PARP1, inhibiting ionophore-induced necrosis. Strikingly, all of this occurs in the absence of detectable DNA damage and signaling up to 8 hours after ionophore treatment. Furthermore, little AIF was released from mitochondria/cytoplasm for nuclear import, supporting the necrotic type of cell death in the early period of the treatments. Our results reveal a novel ATR-mediated anti-necrotic mechanism in the cellular stress response to calcium influx without DNA damage signaling.
AB - Hyperactivation of PARP1 is known to be a major cause of necrotic cell death by depleting NAD+/ATP pools during Ca2+ overload which is associated with many ischemic diseases. However, little is known about how PARP1 hyperactivity is regulated during calcium overload. In this study we show that ATR kinase, well known for its role in DNA damage responses, suppresses ionomycin, glutamate, or quinolinic acid-induced necrotic death of cells including SH-SY5Y neuronal cells. We found that the inhibition of necrosis requires the kinase activity of ATR. Specifically, ATR binds to and phosphorylates PARP1 at Ser179 after the ionophore treatments. This site-specific phosphorylation inactivates PARP1, inhibiting ionophore-induced necrosis. Strikingly, all of this occurs in the absence of detectable DNA damage and signaling up to 8 hours after ionophore treatment. Furthermore, little AIF was released from mitochondria/cytoplasm for nuclear import, supporting the necrotic type of cell death in the early period of the treatments. Our results reveal a novel ATR-mediated anti-necrotic mechanism in the cellular stress response to calcium influx without DNA damage signaling.
KW - ATR
KW - Ca overload
KW - PARP1
KW - PARP1 phosphorylation
KW - necrosis
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UR - http://www.scopus.com/inward/citedby.url?scp=85103863253&partnerID=8YFLogxK
U2 - 10.1096/fj.202001636RRR
DO - 10.1096/fj.202001636RRR
M3 - Article
C2 - 33811702
AN - SCOPUS:85103863253
SN - 0892-6638
VL - 35
JO - FASEB Journal
JF - FASEB Journal
IS - 5
M1 - e21373
ER -