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

Kevin Brown and colleagues functionally characterize a melanoma risk locus encompassing PARP1 , correlating the risk genotype to PARP1 gene expression levels in melanoma cells. They identify an intronic gene-regulatory variant in PARP1 and find that PARP1 can promote cell proliferation and rescue on...

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Bibliographic Details
Published in:	Nature genetics Vol. 49; no. 9; pp. 1326 - 1335
Main Authors:	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
Format:	Journal Article
Language:	English
Published:	New York Nature Publishing Group US 01-09-2017 Nature Publishing Group
Subjects:	38/43 45/15 631/208/200 631/208/205/2138 631/67/1813/1634 692/308/2056 692/699/67/1813/1634 Agriculture Alleles Animal Genetics and Genomics Base Sequence Biomedicine Cancer Cancer Research 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 Function Gene mapping Genetic aspects Genome-wide association studies Genomes Human Genetics 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 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 United States United Kingdom
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Summary:	Kevin Brown and colleagues functionally characterize a melanoma risk locus encompassing PARP1 , correlating the risk genotype to PARP1 gene expression levels in melanoma cells. They identify an intronic gene-regulatory variant in PARP1 and find that PARP1 can promote cell proliferation and rescue oncogene-induced senescence, likely through 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; r 2 = 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 V600E -induced senescence phenotypes in a PARylation-independent manner. PARP1 also transformed TERT -immortalized melanocytes expressing BRAF V600E . PARP1-mediated senescence rescue was accompanied by transcriptional activation of the melanocyte-lineage survival oncogene MITF , highlighting a new role for PARP1 in melanomagenesis.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1061-4036 1546-1718 1546-1718
DOI:	10.1038/ng.3927