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的常见内含子变体赋予黑色素瘤风险，并通过调节MITF介导黑色素细胞的生长。

先前的全基因组关联研究已在1q42.1处发现了与黑色素瘤相关的基因座，该基因座涵盖了跨越PARP1基因的100 kb区域。在黑色素细胞谱系的多种细胞类型中的表达定量性状基因座（eQTL）分析一致表明，1q42.1黑色素瘤风险等位基因（rs3219090 [G]）与更高的PARP1水平相关。在计算机上精细映射和功能验证确定了一个常见的内含子插入缺失rs144361550（-/ GGGCCC； r2 = 0.947，带有rs3219090），显示了等位基因特异性的转录活性。蛋白质组学筛选确定RECQL以等位基因优先方式与rs144361550结合。在人类原代黑素细胞中，PARP1以不依赖PARylation的方式促进细胞增殖并拯救BRAFV600E诱导的衰老表型。PARP1还转化了表达BRAFV600E的TERT永生黑色素细胞。PARP1介导的衰老抢救伴随着黑色素细胞谱系生存癌基因MITF的转录激活，突出了PARP1在黑色素瘤发生中的新作用。