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.

中文翻译：

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PARP1 的常见内含子变异会带来黑色素瘤风险，并通过 MITF 的调节介导黑色素细胞生长。


先前的全基因组关联研究已在 1q42.1 确定了一个与黑色素瘤相关的位点，该位点包含跨越 PARP1 基因的约 100 kb 区域。黑色素细胞谱系多种细胞类型的表达数量性状位点 (eQTL) 分析一致表明，1q42.1 黑色素瘤风险等位基因 (rs3219090[G]) 与较高的 PARP1 水平相关。在计算机精细定位和功能验证中，确定了一个常见的内含子插入缺失，rs144361550（-/GGGCCC；r2 = 0.947，rs3219090），显示出等位基因特异性转录活性。蛋白质组筛选鉴定 RECQL 以等位基因优先方式与 rs144361550 结合。在人原代黑素细胞中，PARP1 以不依赖于 PARylation 的方式促进细胞增殖并挽救 BRAFV600E 诱导的衰老表型。 PARP1 还转化了表达 BRAFV600E 的 TERT 永生化黑素细胞。 PARP1 介导的衰老拯救伴随着黑色素细胞谱系存活癌基因 MITF 的转录激活，突显了 PARP1 在黑色素瘤发生中的新作用。