Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0043346 (xeroderma pigmentosum)
 2,924 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The repair of cyclobutane pyrimidine dimers was measured under non-replicating conditions in a 2054-bp fragment of a cAMP-inducible cysteine proteinase (CP2) gene in D. discoideum. Overall genomic repair was unaffected by cAMP. The removal of dimers from CP2 in the wild-type NP2 cells as quantified using T4 endonuclease V was independent of transcription and was the same as in the overall genome. In a UV-sensitive radC mutant in which the rate of overall dimer removal was previously shown to be reduced, the initial rate of dimer removal in the uninduced CP2 gene (-cAMP) was 3-fold lower compared to the induced gene (+cAMP), in which repair was identical to that for the induced and uninduced states of NP2. D. discoideum may have two pathways for repairing dimers. One, effective in the wild-type strain but of reduced efficiency in radC repairs dimers equally well independent of transcription and at about the same rate as in the overall genome. A second pathway, retained in radC, repairs dimers more slowly in the overall genome and in the uninduced CP2 gene while undergoing the wild-type rate of repair in the transcriptionally active gene. Hence radC has reduced ability to repair transcriptionally inactive DNA, a defect similar to that of xeroderma pigmentosum group C.
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PMID:Differential repair of UV damage in a developmentally regulated gene of Dictyostelium discoideum. 751 Mar 68

An ultraviolet (UV)-resistant F9 variant cell line, termed F9Vc, was established from a prolonged culture of murine F9 embryonic stem cells. A 6-fold UV resistance was detected in F9V2 cells compared to the F9 parental cells, as determined by ID50 (36 J/m2 vs. 6 J/m2), the UV dose causing 50% growth inhibition. Using a DNA mobility-shift assay, a nuclear protein (termed UVDRP) that preferentially binds to UV-damaged DNA was detected in F9 and F9Vc cell extracts. The UVDRP in F9Vc cells was present at a 7-fold higher concentration than that of F9 cells. Interestingly, the F9 UVDRP was transiently induced following cellular differentiation by retinoic acid (RA)/cAMP, with optimum induction (15-fold) at 6 days. Although constitutively over-produced, UVDRP also remained inducible in F9Vc cells in response to RA/cAMP. Indirect DNA repair measurement by host cell reactivation of UV-damaged plasmid DNA demonstrated that F9Vc cells exhibited a slight increase or a similarity in repair ability compared to the F9 cells. Parallel experiments using the repair-defective xeroderma pigmentosum (XP) group A fibroblasts and the normal VA13 fibroblasts also indicated that over-production of UVDRP binding activity was associated with enhanced DNA repair and UV resistance. The findings indicate that prolonged culture of F9 cells can establish a condition sufficient to cause constitutive over-production of UVDRP binding activity and UV resistance. The results also suggest that the RA/cAMP-inducible UVDRP in F9 stem cells may be important for the sensitivity or resistance of the cells to UV damage.
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PMID:Constitutive over-production of DNA-damage recognition proteins and acquired UV resistance in prolonged culture of F9 teratocarcinoma stem cells. 836 66

The melanocortin 1 receptor (MC1R), which signals through cAMP, is a melanocytic transmembrane receptor involved in pigmentation, adaptive tanning, and melanoma resistance. We report MC1R-mediated or pharmacologically-induced cAMP signaling promotes nucleotide excision repair (NER) in a cAMP-dependent protein kinase A (PKA)-dependent manner. PKA directly phosphorylates ataxia telangiectasia and Rad3-related protein (ATR) at Ser435, which actively recruits the key NER protein xeroderma pigmentosum complementation group A (XPA) to sites of nuclear UV photodamage, accelerating clearance of UV-induced photolesions and reducing mutagenesis. Loss of Ser435 within ATR prevents PKA-mediated ATR phosphorylation, disrupts ATR-XPA binding, delays recruitment of XPA to UV-damaged DNA, and elevates UV-induced mutagenesis. This study mechanistically links cAMP-PKA signaling to NER and illustrates potential benefits of cAMP pharmacological rescue to reduce UV mutagenesis in MC1R-defective, melanoma-susceptible individuals.
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PMID:PKA-mediated phosphorylation of ATR promotes recruitment of XPA to UV-induced DNA damage. 2495 Mar 77

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.
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PMID:The melanocortin signaling cAMP axis accelerates repair and reduces mutagenesis of platinum-induced DNA damage. 2891 31

Blunted melanocortin 1 receptor (MC1R) signaling promotes melanocyte genomic instability in part by attenuating cAMP-mediated DNA repair responses, particularly nucleotide excision repair (NER), which recognizes and clears mutagenic photodamage. cAMP-enhanced NER is mediated by interactions between the ataxia telangiectasia-mutated and Rad3-related (ATR) and xeroderma pigmentosum complementation group A (XPA) proteins. We now report a critical role for sirtuin 1 (SIRT1) in regulating ATR-mediated phosphorylation of XPA. SIRT1 deacetylates XPA at residues Lys-63, Lys-67, and Lys-215 to promote interactions with ATR. Mutant XPA containing acetylation mimetics at residues Lys-63, Lys-67, and Lys-215 exhibit blunted UV-dependent ATR-XPA interactions even in the presence of cAMP signals. ATR-mediated phosphorylation of XPA on Ser-196 enhances cAMP-mediated optimization of NER and is promoted by SIRT1-mediated deacetylation of XPA on Lys-63, Lys-67, and Lys-215. Interference with ATR-mediated XPA phosphorylation at Ser-196 by persistent acetylation of XPA at Lys-63, Lys-67, and Lys-215 delays repair of UV-induced DNA damage and attenuates cAMP-enhanced NER. Our study identifies a regulatory ATR-SIRT1-XPA axis in cAMP-mediated regulation melanocyte genomic stability, involving SIRT1-mediated deacetylation (Lys-63, Lys-67, and Lys-215) and ATR-dependent phosphorylation (Ser-196) post-translational modifications of the core NER factor XPA.
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PMID:Sirtuin 1-mediated deacetylation of XPA DNA repair protein enhances its interaction with ATR protein and promotes cAMP-induced DNA repair of UV damage. 3303 83