Functional Polymorphism in Pak1–3′ Untranslated Region Alters Skin Tumor Susceptibility by Alternative Polyadenylation

We identified a functional SNP in the 3' untranslated region of Pak1 that is responsible for the skin tumor modifier of MSM 1a locus. Candidate SNPs in the 3' untranslated region of Pak1 from resistance strain MSM/Ms were introduced into susceptible strain FVB/N using CRISPR/Cas9. The 7,12-dimethylbenz(a)anthracene/12-O-tetradecanoylphorbol-13-acetate skin carcinogenesis experiments revealed an SNP (Pak1-3' untranslated region-6(C>T): rs31627325) that strongly suppressed skin tumors. Furthermore, MBNL1 bound more strongly to FVB-allele (6(C/C)) and regulated the transcript length in the 3' untranslated region of Pak1 and tumorigenesis through polyadenylation. Therefore, the alternative polyadenylation of Pak1 is cis-regulated by rs31627325.