Nature Genetics 2017

In July 2017, Matthew MakowskiMichiel Vermeulen (Radboud University, Nijmegen, The Netherlands) and collaborators published a paper in Nature Genetics.

 

Choi J, Xu M, Makowski MM, Zhang T, Law MH, Kovacs MA, Granzhan A, Kim WJ, Parikh H, Gartside M, Trent JM, Teulade-Fichou MP, Iles MM, Newton-Bishop JA, Bishop DT, MacGregor S, Hayward NK, Vermeulen M, Brown KM. A common intronic variant of PARP1 confers melanoma risk and mediates melanocyte growth via regulation of MITF. Nat Genet. 2017 Jul 31. doi: 10.1038/ng.3927.

 

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.