A Common Intronic Variant of PARP1 Confers Melanoma Risk and Mediates Melanocyte Growth via Regulation of MITF

Nat Genet. 2017 Sep;49(9):1326-1335. doi: 10.1038/ng.3927. Epub 2017 Jul 31.

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 / genetics*
  • Cell Transformation, Neoplastic / genetics
  • Cells, Cultured
  • Cellular Senescence / genetics
  • Gene Expression Profiling / methods
  • Gene Expression Regulation, Neoplastic
  • Humans
  • INDEL Mutation
  • Immunoblotting
  • Introns / genetics*
  • Melanocytes / metabolism*
  • Melanoma / genetics
  • Melanoma / metabolism
  • Melanoma / pathology
  • Microphthalmia-Associated Transcription Factor / genetics*
  • Microphthalmia-Associated Transcription Factor / metabolism
  • Microscopy, Confocal
  • Poly (ADP-Ribose) Polymerase-1 / genetics*
  • Poly (ADP-Ribose) Polymerase-1 / metabolism
  • Polymorphism, Single Nucleotide*
  • Proto-Oncogene Proteins B-raf / genetics
  • Proto-Oncogene Proteins B-raf / metabolism
  • Risk Factors
  • Telomerase / genetics
  • Telomerase / metabolism

Substances

  • MITF protein, human
  • Microphthalmia-Associated Transcription Factor
  • PARP1 protein, human
  • Poly (ADP-Ribose) Polymerase-1
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
  • TERT protein, human
  • Telomerase