A common intronic variant of PARP1 confers melanoma risk and mediates melanocyte growth via regulation of MITF.
Nat Genet, 2017/9;49(9):1326-1335.
Choi J[1], Xu M[1], Makowski MM[2], Zhang T[1], Law MH[3], Kovacs MA[1], Granzhan A[4], Kim WJ[1], Parikh H[1, 5], Gartside M[3], Trent JM[6], Teulade-Fichou MP[4], Iles MM[7], Newton-Bishop JA[7], Bishop DT[7], MacGregor S[3], Hayward NK[3], Vermeulen M[2], Brown KM[1]
Affiliations
PMID: 28759004DOI: 10.1038/ng.3927
Impact factor: 41.307
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.
MeSH terms
Base Sequence; Cell Line, Tumor; Cell Proliferation; Cell Transformation, Neoplastic; Cells, Cultured; Cellular Senescence; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; INDEL Mutation; Immunoblotting; Introns; Melanocytes; Melanoma; Microphthalmia-Associated Transcription Factor; Microscopy, Confocal; Poly (ADP-Ribose) Polymerase-1; Polymorphism, Single Nucleotide; Proto-Oncogene Proteins B-raf; Risk Factors; Telomerase
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