RETRACTED ARTICLE: The melanocortin signaling cAMP axis accelerates repair and reduces mutagenesis of platinum-induced DNA damage

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.

Sirtuin 1-mediated deacetylation of XPA DNA repair protein enhances its interaction with ATR protein and promotes cAMP-induced DNA repair of UV damage

“…Briefly, we found that in the context of cell damage and cAMP activation, PKA phosphorylates ATR (17). PKA-mediated ATR phosphorylation on Ser-435 promotes interactions between XPA and ATR and accelerates their recruitment to UV photodamage (17) or platinum adducts (43). Because our earlier work documented that cAMP-enhanced NER depended on ATR-XPA interactions (17), we considered whether other post-translational modifications in ATR or XPA might regulate this pathway.…”

Mahogunin Ring Finger 1 Is Required for Genomic Stability and Modulates the Malignant Phenotype of Melanoma Cells

“…This might account, at least partially, for the milder phenotype of Mgrn1 -KO cells newly derived from melan-a6 or B16 cells, as compared with melan-md1 cells derived from mahoganoid mice. Interestingly, human MC1R, a GPCR that activates DNA damage repair in melanocytes [ 52 , 53 , 54 , 55 ] (reviewed in [ 56 , 57 ]) interacts with MGRN1 and promotes its nuclear localization [ 13 ]. Given that activation of MC1R in human melanoma cells stimulates the clearance of DNA strand breaks generated by oxidative stress [ 45 ], a possible involvement of MGRN1 in this MC1R-dependent genoprotective action cannot be ruled out and deserves further analysis.…”

Protective effects of novel derivatives of vitamin D3 and lumisterol against UVB-induced damage in human keratinocytes involve activation of Nrf2 and P53 defense mechanisms

“…Since, Nrf2-antioxidant signaling has a well-established key role in protection against UV-mediated skin damage [17,56], we further investigated the protective effect of the vitamin D 3 and lumisterol derivatives against UVB-mediated oxidative stress by Nrf2-regulated antioxidant responses. A marked reduction in catalase (P < 0.001, Fig.…”