| Literature DB >> 28759004 |
Jiyeon Choi1, Mai Xu1, Matthew M Makowski2, Tongwu Zhang1, Matthew H Law3, Michael A Kovacs1, Anton Granzhan4, Wendy J Kim1, Hemang Parikh1,5, Michael Gartside3, Jeffrey M Trent6, Marie-Paule Teulade-Fichou4, Mark M Iles7, Julia A Newton-Bishop7, D Timothy Bishop7, Stuart MacGregor3, Nicholas K Hayward3, Michiel Vermeulen2, Kevin M Brown1.
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.Entities:
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Year: 2017 PMID： 28759004 DOI： 10.1038/ng.3927
Source DB: PubMed Journal: Nat Genet ISSN： 1061-4036 Impact factor: 38.330