RETRACTED ARTICLE: The melanocortin signaling cAMP axis accelerates repair and reduces mutagenesis of platinum-induced DNA damage
Authors: Stuart G Jarrett
John A D&#x27;Orazio
Brent J Shelton
Katharine M Carter
Journal: Scientific Reports (2017)
Discipline: Multidisciplinary
Keywords: cAMP signaling; platinum-induced DNA damage; repair; melanocytes; MC1R
Affiliations: The Markey Cancer Center, University of Kentucky College of Medicine, Lexington, Kentucky, 40536, USA., Department of Toxiciology and Cancer Biology, University of Kentucky College of Medicine, Lexington, Kentucky, 40536, USA., Department of Cancer Biostatistics, University of Kentucky College of Medicine, Lexington, Kentucky, 40536, USA., The Markey Cancer Center, University of Kentucky College of Medicine, Lexington, Kentucky, 40536, USA. .

Abstract:  Using primary melanocytes and HEK293 cells, we found that cAMP signaling accelerates repair of bi- and mono-functional platinum-induced DNA damage. Elevating cAMP signaling either by the agonistic MC1R ligand melanocyte stimulating hormone (MSH) or by pharmacologic cAMP induction by forskolin enhanced clearance of intrastrand cisplatin-adducts in melanocytes or MC1R-transfected HEK293 cells. MC1R antagonists human beta-defensin 3 and agouti signaling protein blocked MSH- but not forskolin-mediated enhancement of platinum-induced DNA damage. cAMP-enhanced repair of cisplatin-induced DNA damage was dependent on PKA-mediated phosphorylation of ATR on S435 which promoted ATR's interaction with the key NER factor xeroderma pigmentosum A (XPA) and facilitated recruitment of an XPA-ATR-pS435 complex to sites of cisplatin DNA damage. Moreover, we developed an oligonucleotide retrieval immunoprecipitation (ORiP) assay using a novel platinated-DNA substrate to establish kinetics of ATR-pS435 and XPA's associations with cisplatin-damaged DNA. Expression of a non-phosphorylatable ATR-S435A construct or deletion of A kinase-anchoring protein 12 (AKAP12) impeded platinum adduct clearance and prevented cAMP-mediated enhancement of ATR and XPA's associations with cisplatin-damaged DNA, indicating that ATR phosphorylation at S435 is necessary for cAMP-enhanced repair of platinum-induced damage and protection against cisplatin-induced mutagenesis. These data implicate cAMP signaling as a critical regulator of genomic stability against platinum-induced mutagenesis. 

Retracted: Yes

PubPeer comments:
 2021retraction. https: www.nature.com articles s41598-020-80467-y Retraction of: Scientific Reports https: doi.org 10.1038 s41598-017-12056-5, published online 15 September 2017 The authors are retracting this article. An investigation by the University of Kentucky College of Medicine, where the research was conducted, has concluded that several panels depicted in Figure 5A present false or fabricated data, namely: the PLA images in columns 1 and 4 of the u201c- Cisplatinu201d condition are blank black panels without any data signal the DAPI image for the u201cMSHu2009+u2009HBD3u2009+u2009Cisplatinu201d condition is a duplicate of the DAPI image for the u201cMSHu2009+u2009Cisplatinu201d condition In addition, the authors were not able to locate all the original data files. The results and conclusions in this article are therefore unreliable. Katharine M. Carter, Brent J. Shelton John A. Du2019Orazio agree with the retraction and its wording. Stuart G. Jarrett did not respond to the correspondence about the retraction. ,