Nature genetics, 2017-09, Vol.49 (9), p.1326-1335
- Choi, Jiyeon
- Xu, Mai
- Makowski, Matthew M
- Zhang, Tongwu
- Law, Matthew H
- Kovacs, Michael A
- Granzhan, Anton
- Kim, Wendy J
- Parikh, Hemang
- Gartside, Michael
- Trent, Jeffrey M
- Teulade-Fichou, Marie-Paule
- Iles, Mark M
- Newton-Bishop, Julia A
- Bishop, D Timothy
- MacGregor, Stuart
- Hayward, Nicholas K
- Vermeulen, Michiel
- Brown, Kevin M
2017
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- Autor(en) / Beteiligte
- Choi, Jiyeon
- Xu, Mai
- Makowski, Matthew M
- Zhang, Tongwu
- Law, Matthew H
- Kovacs, Michael A
- Granzhan, Anton
- Kim, Wendy J
- Parikh, Hemang
- Gartside, Michael
- Trent, Jeffrey M
- Teulade-Fichou, Marie-Paule
- Iles, Mark M
- Newton-Bishop, Julia A
- Bishop, D Timothy
- MacGregor, Stuart
- Hayward, Nicholas K
- Vermeulen, Michiel
- Brown, Kevin M
- Titel
- A common intronic variant of PARP1 confers melanoma risk and mediates melanocyte growth via regulation of MITF
- Ist Teil von
- Nature genetics, 2017-09, Vol.49 (9), p.1326-1335
- Ort / Verlag
- United States: Nature Publishing Group
- Erscheinungsjahr
- 2017
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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; r = 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 BRAF -induced senescence phenotypes in a PARylation-independent manner. PARP1 also transformed TERT-immortalized melanocytes expressing BRAF . PARP1-mediated senescence rescue was accompanied by transcriptional activation of the melanocyte-lineage survival oncogene MITF, highlighting a new role for PARP1 in melanomagenesis.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1061-4036, 1546-1718eISSN: 1546-1718DOI: 10.1038/ng.3927Titel-ID: cdi_gale_incontextgauss_ISR_A502334833
- Format
- –
- Schlagworte
- Alleles, Base Sequence, Cancer, Cell Line, Tumor, Cell proliferation, Cell Proliferation - genetics, Cell Transformation, Neoplastic - genetics, Cells, Cultured, Cellular Senescence - genetics, Deoxyribonucleic acid, Development and progression, DNA, DNA damage, DNA methylation, DNA repair, Gene expression, Gene Expression Profiling - methods, Gene Expression Regulation, Neoplastic, Gene mapping, Genetic aspects, Genome-wide association studies, Genomes, Humans, Immunoblotting, INDEL Mutation, Introns - genetics, Melanocytes, Melanocytes - metabolism, Melanoma, Melanoma - genetics, Melanoma - metabolism, Melanoma - pathology, Microphthalmia-associated transcription factor, Microphthalmia-Associated Transcription Factor - genetics, Microphthalmia-Associated Transcription Factor - metabolism, Microscopy, Confocal, Mutation, Physiological aspects, Poly (ADP-Ribose) Polymerase-1 - genetics, Poly (ADP-Ribose) Polymerase-1 - metabolism, Poly(ADP-ribose) Polymerase 1, Polymorphism, Single Nucleotide, Proteomics, Proto-Oncogene Proteins B-raf - genetics, Proto-Oncogene Proteins B-raf - metabolism, Quantitative trait loci, Regression analysis, Risk Factors, RNA polymerase, Senescence, Studies, Telomerase - genetics, Telomerase - metabolism, Transcription activation, Transcription factors