An intronic indel variant enhances RECQL binding to upregulate PARP1 in melanocytic cells.
Major finding: An intronic indel variant enhances RECQL binding to upregulate PARP1 in melanocytic cells.
Mechanism: PARP1 upregulates MITF by directly binding to its promoter to promote melanomagenesis.
Impact: PARP1 may have a poly(ADP-ribosyl)ation independent role in activating MITF to facilitate melanoma growth.
Genome-wide association studies (GWAS) have shown that 1q42.1 is a melanoma-associated locus that spans an approximately 100 kb region containing a number of genes including PARP1. In order to functionally characterize the 1q42.1 risk locus, Choi, Xu, and colleagues performed eQTL analysis to determine which genes are associated with melanoma risk. The rs3219090[G] risk allele was associated with increased expression of PARP1 in melanoma and skin cells, and, in cells heterozygous for the risk allele, there was an allelic imbalance with the majority of the PARP1 expressed from the risk allele. Fine-mapping and functional annotation of candidate SNPs revealed an absence of variants predicted to change the PARP1 amino acid sequence. Further characterization of candidate functional variants found that an intronic GGGCCC/- indel variant, rs144361550, exhibits allelic transcriptional activity in melanoma cells. The helicase RECQL bound in an allele-specific manner to rs144361550 and promoted PARP1 transcription. PARP1 overexpression promoted the growth of human primary melanocytes, partially rescued them from BRAFV600E-induced senescence, and facilitated oncogenic transformation of immortalized human melanocytes. These effects were independent of the poly(ADP-ribosyl)ation activity of PARP1. Mechanistically, PARP1 bound to the promoter of the melanocyte master regulatory transcription factor MITF, which is often amplified in melanoma and is sufficient to transform BRAFV600E-expressing melanocytes, promoting transcriptional activation of MITF. Collectively, these findings suggest that PARP1-mediated MITF upregulation contributes to the melanoma risk conferred by the 1q42.1 melanoma risk allele rs3219090[G], and support a role for PARP1 in promoting melanoma tumorigenesis.
Choi J, Xu M, Makowski MM, Zhang T, Law MH, Kovacs MA, et al. A common intronic variant of PARP1 confers melanoma risk and mediates melanocyte growth via regulation of MITF. Nat Genet 2017 Jul 31 [Epub ahead of print].
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