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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.

Author information

1
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA.
2
Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Radboud University, Nijmegen, the Netherlands.
3
QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
4
CNRS UMR 9187, INSERM U1196, Institut Curie, PSL Research University and Université Paris Sud, Université Paris Saclay, Orsay, France.
5
Health Informatics Institute, Morsani College of Medicine, University of South Florida, Tampa, Florida, USA.
6
Translational Genomics Research Institute, Phoenix, Arizona, USA.
7
Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK.

Abstract

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.

PMID:
28759004
DOI:
10.1038/ng.3927
[Indexed for MEDLINE]
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