Abstract
<div>Abstract<p>Both genetic mutations and UV irradiation (UVR) can predispose individuals to melanoma. Although BRAF<sup>V600E</sup> is the most prevalent oncogene in melanoma, the BRAF<sup>V600E</sup> mutant is not sufficient to induce tumors <i>in vivo</i>. Mutation at the <i>CDKN2A</i> locus is another melanoma-predisposing event that can disrupt the function of both p16<sup>INK4a</sup> and ARF. Numerous studies have focused on the role of p16<sup>INK4a</sup> in melanoma, but the involvement of ARF, a well-known p53 activator, is still controversial. Using a transgenic BRAF<sup>V600E</sup> mouse model previously generated in our laboratory, we report that loss of ARF is able to enhance spontaneous melanoma formation and cause profound sensitivity to neonatal UVB exposure. Mechanistically, BRAF<sup>V600E</sup> and ARF deletion synergize to inhibit nucleotide excision repair by epigenetically repressing XPC and inhibiting the E2F4/DP1 complex. We suggest that the deletion of ARF promotes melanomagenesis not by abrogating p53 activation but by acting in concert with BRAF<sup>V600E</sup> to increase the load of DNA damage caused by UVR. <i>Cancer Res; 73(14); 4337–48. ©2013 AACR</i>.</p></div>
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