ATR Plays a Direct Antiapoptotic Role at Mitochondria, which Is Regulated by Prolyl Isomerase Pin1
Open accessAbstract
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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The anti-apoptotic function of mitochondrial ATR-H is independent of its checkpoint kinase activity.
“Also, the anti-apoptotic function of mitochondrial ATR-H is independent of its checkpoint kinase activity 40, 41.”
From Xeroderma Pigmentosa Group A (XPA), Nucleotide Excision Repair and Regulation by ATR in Response to Ultraviolet Irradiation (2017) · cites this paper as [40]
A small fraction of cellular ATR normally exists in the cytoplasm, and DNA-damaging agents increase this cytoplasmic ATR and change it to a slower-migrating ATR-H form.
“It was demonstrated that in mammals a small fraction of cellular ATR normally exists in the cytoplasm (cytoATR) and that, in response to DNA damaging agents, the amount of this cytoATR increases and changes conformation, resulting in a slower-migrating, higher electrophoretic band (ATR-H) as compared with the faster-migrating, lower electrophoretic band (ATR-L).”
From Xeroderma Pigmentosa Group A (XPA), Nucleotide Excision Repair and Regulation by ATR in Response to Ultraviolet Irradiation (2017) · cites this paper as [40]
UV irradiation is the most efficient inducer of ATR-H formation, although camptothecin and hydroxyurea also induce it.
“The most efficient induction of ATR-H formation was by UV irradiation, though it also was induced by camptothecin and hydroxyurea, agents which cause DNA double-strand breaks (DSBs).”
From Xeroderma Pigmentosa Group A (XPA), Nucleotide Excision Repair and Regulation by ATR in Response to Ultraviolet Irradiation (2017) · cites this paper as [40]
The persistence of ATR-H for over 8 hours gives most NER-competent cells enough time to repair all 6-4 PP adducts and most or all CPD adducts.
“Note that, once formed, ATR-H reaches a maximum within 2 hours but persists in the cytoplasm for over 8 hours, sufficient time for most NER-competent cells to repair all the (6–4) PP adducts and most, if not all, of the CPD adducts 40, 53,41.”
From Xeroderma Pigmentosa Group A (XPA), Nucleotide Excision Repair and Regulation by ATR in Response to Ultraviolet Irradiation (2017) · cites this paper as [40]
ATR-H reaches a maximum within 2 hours but persists in the cytoplasm for over 8 hours.
“Note that, once formed, ATR-H reaches a maximum within 2 hours but persists in the cytoplasm for over 8 hours, sufficient time for most NER-competent cells to repair all the (6–4) PP adducts and most, if not all, of the CPD adducts 40, 53,41.”
From Xeroderma Pigmentosa Group A (XPA), Nucleotide Excision Repair and Regulation by ATR in Response to Ultraviolet Irradiation (2017) · cites this paper as [40]
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1 retracted
RETRACTED: PKA-Mediated Phosphorylation of ATR Promotes Recruitment of XPA to UV-Induced DNA Damage
Jarrett, S. G., Horrell, E. M. W., Christian, P. A., Vanover, J. C., Boulanger, M. C., Zou, Y., & D’Orazio, J. A. (2014) · Molecular Cell · doi:10.1016/j.molcel.2014.05.030 · Cited by 85 · see citing works
Self-citationRetractedMolecular Mechanisms of Mammalian DNA Repair and the DNA Damage Checkpoints
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Sensing DNA Damage Through ATRIP Recognition of RPA-ssDNA Complexes
Zou, L., & Elledge, S. J. (2003) · Science · doi:10.1126/science.1083430 · Cited by 2,693 · see citing works
Mitochondria and cell death: outer membrane permeabilization and beyond
Tait, S. W. G., & Green, D. R. (2010) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2952 · Cited by 2,593 · see citing works
Causes and consequences of replication stress
Zeman, M. K., & Cimprich, K. A. (2014) · Nature Cell Biology · doi:10.1038/ncb2897 · Cited by 2,079 · see citing works
ATR and ATRIP: Partners in Checkpoint Signaling
Cortez, D., Guntuku, S., Qin, J., & Elledge, S. J. (2001) · Science · doi:10.1126/science.1065521 · Cited by 985 · see citing works
<i>ATR</i> disruption leads to chromosomal fragmentation and early embryonic lethality
Brown, E. J., & Baltimore, D. (2000) · Genes & Development · doi:10.1101/gad.14.4.397 · Cited by 951 · see citing works
The prolyl isomerase Pin1 restores the function of Alzheimer-associated phosphorylated tau protein
Lu, P.-J., Wulf, G., Zhou, X. Z., Davies, P., & Lu, K. P. (1999) · Nature · doi:10.1038/21650 · Cited by 721 · see citing works
Self-citationATR autophosphorylation as a molecular switch for checkpoint activation
Liu, S., Shiotani, B., Lahiri, M., Maréchal, A., Tse, A., Leung, C. C. Y., Glover, J. N. M., Yang, X. H., & Zou, L. (2011) · Molecular Cell · doi:10.1016/j.molcel.2011.06.019 · Cited by 281 · see citing works
Heffernan, T. P., Kawasumi, M., Blasina, A., Anderes, K., Conney, A. H., & Nghiem, P. (2009) · Journal of Investigative Dermatology · doi:10.1038/jid.2008.435 · Cited by 95 · cited 2× · see citing works
“Since ATR is well known for its DDR role in the nucleus, including apoptosis suppression via the ATR-Chk1 pathway (Heffernan et al., 2009), this study reveals a Pin1-regulated function of ATR in the cytoplasm.”
Wu, X., Shell, S. M., Yang, Z., & Zou, Y. (2006) · Cancer Research · doi:10.1158/0008-5472.can-05-3403 · Cited by 85 · cited 2× · see citing works
“Phosphatidylinositol 3-kinase (PI3K)-like protein kinase ATR (Ataxia telangiectasia and Rad3 related) plays a critical role in maintaining genome integrity against DNA damage (Cimprich and Cortez, 2008; Sancar et al., 2004; Wu et al., 2006; Zeman and Cimprich, 2014; Zou and Elledge, 2003) and is a central player in pr…”
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Galluzzi, L., Vitale, I., Aaronson, S. A., Abrams, J. M., Adam, D., Agostinis, P., Alnemri, E. S., Altucci, L., Amelio, I., Andrews, D. W., et al. (2018) · Cell Death & Differentiation · doi:10.1038/s41418-017-0012-4 · Cited by 6,680 · see citing works
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Sondka, Z., Bamford, S., Cole, C. G., Ward, S. A., Dunham, I., & Forbes, S. A. (2018) · Nature Reviews Cancer · doi:10.1038/s41568-018-0060-1 · Cited by 1,597 · see citing works
Acetylation regulates ribonucleotide reductase activity and cancer cell growth
Chen, G., Luo, Y., Warncke, K., Sun, Y., Yu, D. S., Fu, H., Behera, M., Ramalingam, S. S., Doetsch, P. W., Duong, D. M., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-11214-9 · Cited by 82 · see citing works
Musich, P. R., Li, Z., & Zou, Y. (2017) · Advances in Experimental Medicine and Biology · doi:10.1007/978-3-319-56017-5_4 · Cited by 23 · see citing works
Self-citationRetracted: AKAP12 mediates PKA-induced phosphorylation of ATR to enhance nucleotide excision repair
Jarrett, S. G., Wolf Horrell, E. M., & D'Orazio, J. A. (2016) · Nucleic Acids Research · doi:10.1093/nar/gkw871 · Cited by 23 · see citing works
Retracted
- Authors
- Hilton, B. A., Li, Z., Musich, P. R., Wang, H., Cartwright, B. M., Serrano, M., Zhou, X. Z., Lu, K. P., & Zou, Y.
- Affiliations
- East Tennessee State University (US)
- Beth Israel Deaconess Medical Center (US)
- Corresponding author
- Zou, Yue
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2015-10
- Volume
- 60
- Issue
- 1
- Pages
- 35-46
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC4592481
- OpenAlex
- W2103451229
- Cited by
- 95
- References
- 11
- Citations by year
- 2026: 5 · 2025: 9 · 2024: 10 · 2023: 10 · 2022: 9 · 2021: 4 · 2020: 11 · 2019: 8 · 2018: 13 · 2017: 10 · 2016: 5 · 2015: 1
- FWCI
- 4.20
- Type
- journal article
- Language
- en
- Update notices
- erratum (2016-02-04)
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Digital Commons - East Tennessee State University (East Tennessee State University) (submittedVersion)
- Funders
- Vanderbilt University
- National Institute on Aging (R01AG017870)
- National Cancer Institute (R01CA86927, R01CA167677, R01CA086927)
- National Institute of General Medical Sciences (R15GM112168)
- National Center for Research Resources (C06RR0306551)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Keywords
- ATR kinase, Pin1, peptidyl-prolyl isomerase, cytochrome c release, apoptosis, UV damage, cis-trans isomerization, DAPK1, ATRIP, DNA damage response
- MeSH terms
- NIMA-Interacting Peptidylprolyl Isomerase, Binding Sites, DNA Damage, Gene Expression Regulation, Humans, Mitochondria, Protein Conformation, Apoptosis, Peptidylprolyl Isomerase, Cytochromes c, HCT116 Cells, Cell Line, Tumor, BH3 Interacting Domain Death Agonist Protein, bcl-2-Associated X Protein, HEK293 Cells, Ataxia Telangiectasia Mutated Proteins
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