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<title>An intronic indel confers melanoma risk through PARP1 expression regulation | NIH Research Festival</title>
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<article><div class="banner banner--gray banner--compact" style="--banner-background-image: url('/sites/default/files/media/image/2021-03/2015.jpg');--banner-background-focus: 50% 50%"><div class="banner__wrapper"><div class="banner__container"><h2 class="banner__heading">NIH Research Festival</h2><div class="banner__content"><p><strong><time datetime="2015-09-16">September 16</time> – <time datetime="2015-09-18">18, 2015</time></strong></p></div></div></div></div></article>
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<div class="section"><div data-drupal-messages-fallback class="hidden"></div></div><main role="main"><div id="main-content" tabindex="-1"></div><div class="section"><div class="content-sidebar"><div class="content-sidebar__main"><div class="content-sidebar__main-content"><div id="block-mainpagecontent-2"><article><h1>An intronic indel confers melanoma risk through PARP1 expression regulation</h1><div class="schedule"><div class="schedule__label"><div class="schedule__label-text"><time datetime="2015-09-18">Friday, September 18, 2015</time>
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– Poster Session IV
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</div></div><div class="schedule__content"><div class="schedule__item"><div class="schedule__time">12:00 – 1:30 p.m.</div><div class="schedule__description"><p><strong>FAES Terrace</strong></p></div><div class="schedule__description"><p><strong>NCI</strong></p></div><div class="schedule__description"><p><strong>GEN-7</strong></p></div></div></div></div><p><strong>FARE Award Winner</strong></p><h2>Authors</h2><ul><li>J Choi</li><li>M Makowski</li><li>T Zhang</li><li>M Law</li><li>C Sutherland</li><li>M Kovacs</li><li>W Kim</li><li>H Parikh</li><li>L Aoude</li><li>M Gartside</li><li>J Trent</li><li>L Hurley</li><li>M Vermeulen</li><li>S Macgregor</li><li>N Hayward</li><li>M Xu</li><li>K Brown</li></ul><h2>Abstract</h2><p>Genome wide association studies identified several new loci for melanoma susceptibility including chr1q42.1 locus encompassing Poly [ADP-ribose] polymerase 1 (PARP1). To identify effecter genes and functional risk variants from this locus we performed expression quantitative trait loci analysis in 62 melanoma cell lines. The results demonstrated that increased PARP1 levels are correlated with the risk allele (p=0.03). Further allelic imbalance analysis of PARP1 transcripts in 14 melanoma cell lines and 51 TCGA melanomas heterozygous for the lead SNP indicated higher proportion for the risk allele (p=.0001, and .028, respectively). To identify functional risk variants mediating these effects we annotated the locus using six melanoma relevant cell types from ENCODE. Based on single-SNP model as suggested by fine-mapping analysis we prioritized high LD variants for nomination. Among 65 SNPs of r2>0.6 with the lead SNP four exhibited strong evidence as potential transcriptional enhancers. Among them an indel (-/GGGCCC) in the first intron displayed allelic functionality, where melanoma-associated deletion allele displayed higher luciferase activity but insertion allele specifically bound nuclear proteins in vitro. Subsequent mass-spectrometry for these insertion-binding proteins identified a striking collection of Guanine-quadruplex binding proteins including RECQL. RECQL knockdown leads to increased PARP1 expression in melanoma cell lines carrying insenrtion allele. Over-expression of RECQL also results in more pronounced allelic difference in luciferase activities indicating that RECQL contributes to allelic PARP1 expression. These data demonstrate that increased PARP1 expression is correlated with melanoma risk and an indel mediates differential PARP1 expression possibly through secondary DNA structure binding proteins including RECQL.</p><p><strong>Scientific Focus Area</strong>: Genetics and Genomics</p><p class="updated"><small>This page was last updated on Friday, March 26, 2021</small></p></article>
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