Retracted: AKAP12 mediates PKA-induced phosphorylation of ATR to enhance nucleotide excision repair
Open accessAbstract
Loss-of-function in melanocortin 1 receptor (MC1R), a GS protein-coupled receptor that regulates signal transduction through cAMP and protein kinase A (PKA) in melanocytes, is a major inherited melanoma risk factor. Herein, we report a novel cAMP-mediated response for sensing and responding to UV-induced DNA damage regulated by A-kinase-anchoring protein 12 (AKAP12). AKAP12 is identified as a necessary participant in PKA-mediated phosphorylation of ataxia telangiectasia mutated and Rad3-related (ATR) at S435, a post-translational event required for cAMP-enhanced nucleotide excision repair (NER). Moreover, UV exposure promotes ATR-directed phosphorylation of AKAP12 at S732, which promotes nuclear translocation of AKAP12–ATR-pS435. This complex subsequently recruits XPA to UV DNA damage and enhances 5΄ strand incision. Preventing AKAP12's interaction with PKA or with ATR abrogates ATR-pS435 accumulation, delays recruitment of XPA to UV-damaged DNA, impairs NER and increases UV-induced mutagenesis. Our results define a critical role for AKAP12 as an UV-inducible scaffold for PKA-mediated ATR phosphorylation, and identify a repair complex consisting of AKAP12–ATR-pS435-XPA at photodamage, which is essential for cAMP-enhanced NER.
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Activated ATR phosphorylates downstream mediators including Chk1, AKAP12, MK2, p53, ATRIP, and XPA.
“Activated ATR kinase phosphorylates many downstream mediators/effectors which include checkpoint kinase 1 (Chk1), A-kinase-anchoring protein 12 (AKAP12), p38/mitogen-activated protein kinase-activated protein (MAPKAP) kinase 2 (MK2), the tumor suppressor protein p53, ATRIP and XPA 27, 31–33.”
From Xeroderma Pigmentosa Group A (XPA), Nucleotide Excision Repair and Regulation by ATR in Response to Ultraviolet Irradiation (2017) · cites this paper as [31]
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RetractedRETRACTED: PKA-Mediated Phosphorylation of ATR Promotes Recruitment of XPA to UV-Induced DNA Damage
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- [53]Jarrett S.G. Wolf Horrell E.M. Boulanger M.C. D'Orazio J.A. Defining the contribution of MC1R physiological ligands to ATR phosphorylation at Ser435, a predictor of DNA repair in melanocytes J. Invest. Dermatol. 2015 135 3086 3095 26168232 PMC4648643
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Self-citationRoles of UVA radiation and DNA damage responses in melanoma pathogenesis
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Self-citationRetracted
- Authors
- Jarrett, S. G., Wolf Horrell, E. M., & D'Orazio, J. A.
- Affiliations
- University of Kentucky (US)
- Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY 40536, USA
- Corresponding author
- D'Orazio, John A.
- Venue
- Nucleic Acids Research
- Publisher
- Oxford University Press (OUP)
- Published
- 2016-09-28
- Volume
- 44
- Issue
- 22
- Pages
- 10711-10726
- ISSN
- 0305-1048 (ISSN-L)
- 1362-4962
- PMC
- PMC5159552
- OpenAlex
- W2525360026
- Cited by
- 23
- References
- 63
- Citations by year
- 2024: 1 · 2022: 1 · 2021: 1 · 2020: 4 · 2019: 1 · 2018: 7 · 2017: 8
- FWCI
- 2.77
- Type
- journal article
- Language
- en
- Status
- Retracted
- Update notices
- retraction (2020-10-22)
- Open access
- gold
- doi.org
- Licence
- Locations
- Nucleic Acids Research (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- UKnowledge (University of Kentucky) (submittedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- Melanoma Research Alliance
- National Cancer Institute (R01CA131075, P30CA177558, T32CA165990)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Structure and Function
- Keywords
- AKAP12, protein kinase A, ATR phosphorylation, nucleotide excision repair, UV-induced DNA damage, cAMP signaling, XPA, melanoma, UV mutagenesis, DNA repair complexes, nuclear translocation
- MeSH terms
- DNA Damage, DNA Repair, Humans, Kinetics, Phosphorylation, Protein Processing, Post-Translational, Mutagenesis, Cyclic AMP-Dependent Protein Kinases, Cell Cycle Proteins, Protein Transport, Xeroderma Pigmentosum Group A Protein, A Kinase Anchor Proteins, HEK293 Cells, Ataxia Telangiectasia Mutated Proteins
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