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Nat Genet. 2017 Sep;49(9):1326-1335. doi: 10.1038/ng.3927. Epub 2017 Jul 31.

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

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Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA.
Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Radboud University, Nijmegen, the Netherlands.
QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
CNRS UMR 9187, INSERM U1196, Institut Curie, PSL Research University and Université Paris Sud, Université Paris Saclay, Orsay, France.
Health Informatics Institute, Morsani College of Medicine, University of South Florida, Tampa, Florida, USA.
Translational Genomics Research Institute, Phoenix, Arizona, USA.
Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK.


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.

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