A common intronic variant of PARP1 confers melanoma risk and mediates melanocyte growth via regulation of MITF

Previous genome-wide association studies have identified a melanoma-associated locus at 1q42.1 that encompasses a ~100-kb region spanning the PARP1 gene. Expression quantitative trait locus (eQTL) analysis in multiple cell types of the melanocytic lineage consistently demonstrated that the 1q42.1 melanoma risk allele (rs3219090[G]) is correlated with higher PARP1 levels. In silico fine-mapping and functional validation identified a common intronic indel, rs144361550 (−/GGGCCC; r2 = 0.947 with rs3219090), as displaying allele-specific transcriptional activity. A proteomic screen identified RECQL as binding to rs144361550 in an allele-preferential manner. In human primary melanocytes, PARP1 promoted cell proliferation and rescued BRAFV600E-induced senescence phenotypes in a PARylation-independent manner. PARP1 also transformed TERT-immortalized melanocytes expressing BRAFV600E. PARP1-mediated senescence rescue was accompanied by transcriptional activation of the melanocyte-lineage survival oncogene MITF, highlighting a new role for PARP1 in melanomagenesis

Photodegradation of Bacteriochlorophyll c in Intact Cells and Extracts from^Chlorobium tepidum^,

The photo-stability of bacteriochlorophyll c (Bchlc) in an acetone-methanol-water solution extracted from Chlorobium tepidum and in the chlorosomes of intact Chlorobium tepidum cells is studied. The photo-stability of Bchlc in the chlorosomes is high (quantum yield of photo-degradation phi(D) 8 X 10(-7)). In air-saturated acetone-methanol-water solution the photo-degradation of Bchlc is caused by chemical reaction with the dissolved oxygen, where triplet Bchlc produces singlet oxygen, and singlet oxygen reacts with Bchlc to form stable oxidized linear tetrapyrroles as well as intermediate oxidized bacteriochlorophylls. The intermediate photoproducts degrade to linear tetrapyrroles by the catalytic action of triplet oxygen. The initial quantum yield of photo-degradation is direct proportional to the concentration of Bchlc giving phi(D,O) approximate to 0.011 for a 7 x 10(-6) M solution at an excitation wavelength of 672 nm. In nitrogen-bubbled solution the photo-degradation is dominated by direct photoproduct formation in the triplet state of Bchlc. Long-wavelength absorbing intermediate photoproducts degrade slowly in the dark to short-wavelength absorbing stable photoproducts. The quantum yield of photo-degradation of a de-oxygenated solution was found to be phi(D,0) approximate to 0.0012 for excitation at 672 nm. (C) 2004 Elsevier B.V. All rights reserved

Synthesis of mono-and bibrachial naphthalene-based macrocycles with pyrene or ferrocene units for anion detection

International audienc

Solution and Gas-Phase Stability of DNA Junctions from Temperature-Controlled Electrospray Ionization and Surface-Induced Dissociation

DNA three-way junction (TWJ) structures transiently form during key cellular processes such as transcription, replication, and DNA repair. Despite their significance, the thermodynamics of TWJs, including the influence of strand length, base pair composition, and ligand binding on TWJ stability and dissociation mechanisms, are poorly understood. To address these questions, we interfaced temperature-controlled nanoelectrospray ionization mass spectrometry (TC-nESI-MS) with a cyclic ion mobility spectrometry (cIMS) instrument that was also equipped with a surface-induced dissociation (SID) stage. This novel combination allowed us to investigate the structural intermediates of three TWJ complexes and examine the effects of GC base pairs on their dissociation pathways. We found that two TWJ-specific ligands, 2,7-tris-naphthalene (2,7-TrisNP) and tris-phenoxybenzene (TrisPOB), lead to TWJ stabilization, revealed by an increase in the melting temperature (T-m) by 13 or 26 degrees C, respectively. To gain insights into conformational changes in the gas phase, we employed cIMS and SID to analyze TWJs and their complexes with ligands. Analysis of IM arrival distributions suggested a single-step dissociation of TWJs and their intermediates for the three studied TWJ complexes. Upon ligand binding, a higher SID energy by 3 V (2,7-TrisNP) and 5 V (TrisPOB) was required to induce 50% dissociation of TWJ, compared to 38 V in the absence of ligands. Our results demonstrate the power of utilizing TC-nESI-MS in combination with cIMS and SID for thermodynamic characterization of TWJ complexes and investigation of ligand binding. These techniques are essential for the TWJ design and development as drug targets, aptamers, and structural units for functional biomaterials.ISSN:1520-6882ISSN:0003-270

Selective recognition of pyrimidine-pyrimidine DNA mismatches by distance-constrained macrocyclic bis-intercalators

International audienc

Solution and Gas-Phase Stability of DNA Junctions from Temperature-Controlled Electrospray Ionization and Surface-Induced Dissociation

DNA three-way junction (TWJ) structures transiently form during key cellular processes such as transcription, replication, and DNA repair. Despite their significance, the thermodynamics of TWJs, including the influence of strand length, base pair composition, and ligand binding on TWJ stability and dissociation mechanisms, are poorly understood. To address these questions, we interfaced temperature-controlled nanoelectrospray ionization mass spectrometry (TC-nESI-MS) with a cyclic ion mobility spectrometry (cIMS) instrument that was also equipped with a surface-induced dissociation (SID) stage. This novel combination allowed us to investigate the structural intermediates of three TWJ complexes and examine the effects of GC base pairs on their dissociation pathways. We found that two TWJ-specific ligands, 2,7-tris-naphthalene (2,7-TrisNP) and tris-phenoxybenzene (TrisPOB), lead to TWJ stabilization, revealed by an increase in the melting temperature (Tm) by 13 or 26 °C, respectively. To gain insights into conformational changes in the gas phase, we employed cIMS and SID to analyze TWJs and their complexes with ligands. Analysis of IM arrival distributions suggested a single-step dissociation of TWJs and their intermediates for the three studied TWJ complexes. Upon ligand binding, a higher SID energy by 3 V (2,7-TrisNP) and 5 V (TrisPOB) was required to induce 50% dissociation of TWJ, compared to 38 V in the absence of ligands. Our results demonstrate the power of utilizing TC-nESI-MS in combination with cIMS and SID for thermodynamic characterization of TWJ complexes and investigation of ligand binding. These techniques are essential for the TWJ design and development as drug targets, aptamers, and structural units for functional biomaterials