Choi, J, Xu, M, Makowski, MM et al. (16 more authors) (2017) A common intronic variant of PARP1 confers melanoma risk and mediates melanocyte growth via regulation of MITF. Nature Genetics, 49 (9). pp. 1287-1413. ISSN 1061-4036
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.
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Copyright, Publisher and Additional Information: | © 2017 Nature America, Inc., part of Springer Nature. This is an author produced version of a paper published in Nature Genetics. Uploaded in accordance with the publisher's self-archiving policy. | ||||||
Keywords: | Gene regulation; Genetics research; Genome-wide association studies; Melanoma | ||||||
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Institution: | The University of Leeds | ||||||
Academic Units: | The University of Leeds > Faculty of Medicine and Health (Leeds) > Institute of Molecular Medicine (LIMM) (Leeds) > Section of Epidemiology and Biostatistics (Leeds) | ||||||
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Depositing User: | Symplectic Publications | ||||||
Date Deposited: | 18 Jul 2017 09:41 | ||||||
Last Modified: | 31 Jan 2018 01:38 | ||||||
Status: | Published | ||||||
Publisher: | Nature Publishing Group | ||||||
Identification Number: | https://doi.org/10.1038/ng.3927 |