A common intronic variant of PARP1 confers melanoma risk and mediates melanocyte growth via regulation of MITF
Menée in silico et in vitro, cette étude met en évidence le rôle d'un variant intronique de PARP1 dans la croissance des mélanocytes par la régulation de l'activité de MITF, et évalue son association avec le risque de mélanome
Previous genome-wide association studies have identified a melanoma-associated locus at 1q42.1 that encompasses a [sim]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.