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

作者：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^*

来源：Nature Genetics, 2017, 49(9): 1326-+.

DOI：10.1038/ng.3927

Previous genome-wide association studies have identified a melanoma-associated locus at 1q42.1 that encompasses a similar to 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 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.

• 出版日期2017-9