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Mol Cell. 2015 Oct 1;60(1):35-46. doi: 10.1016/j.molcel.2015.08.008. Epub 2015 Sep 18.

ATR Plays a Direct Antiapoptotic Role at Mitochondria, which Is Regulated by Prolyl Isomerase Pin1.

Author information

1
Department of Biomedical Sciences, J.H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA.
2
Department of Medicine, Center for Life Science, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
3
Department of Biomedical Sciences, J.H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA. Electronic address: zouy@etsu.edu.

Abstract

ATR, a PI3K-like protein kinase, plays a key role in regulating DNA damage responses. Its nuclear checkpoint kinase function is well documented, but little is known about its function outside the nucleus. Here we report that ATR has an antiapoptotic activity at mitochondria in response to UV damage, and this activity is independent of its hallmark checkpoint/kinase activity and partner ATRIP. ATR contains a BH3-like domain that allows ATR-tBid interaction at mitochondria, suppressing cytochrome c release and apoptosis. This mitochondrial activity of ATR is downregulated by Pin1 that isomerizes ATR from cis-isomer to trans-isomer at the phosphorylated Ser428-Pro429 motif. However, UV inactivates Pin1 via DAPK1, stabilizing the pro-survival cis-isomeric ATR. In contrast, nuclear ATR remains in the trans-isoform disregarding UV. This cytoplasmic response of ATR may provide a mechanism for the observed antiapoptotic role of ATR in suppressing carcinogenesis and its inhibition in sensitizing anticancer agents for killing of cancer cells.

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PMID:
26387736
PMCID:
PMC4592481
DOI:
10.1016/j.molcel.2015.08.008
[Indexed for MEDLINE]
Free PMC Article

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