Division of Experimental Animal Research, Cancer Genome Center, Chiba Cancer Center Research Institute, Chiba, Japan.
Laboratory of Clinical Omics Research, Department of Applied Genomics, Kazusa DNA Research Institute, Kisarazu, Japan.
J Invest Dermatol. 2022 Sep;142(9):2323-2333.e12. doi: 10.1016/j.jid.2022.02.009. Epub 2022 Mar 1.
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: rs31627325) that strongly suppressed skin tumors. Furthermore, MBNL1 bound more strongly to FVB-allele (6) 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.
我们在 Pak1 的 3' 非翻译区鉴定出一个功能性 SNP，该 SNP 负责 MSM 1a 基因座皮肤肿瘤的修饰。我们使用 CRISPR/Cas9 将来自抗性品系 MSM/Ms 的 Pak1 的 3' 非翻译区中的候选 SNP 导入到易感品系 FVB/N 中。7,12-二甲基苯并(a)蒽/12-O-十四烷酰佛波醇-13-乙酸酯皮肤致癌实验显示出一个 SNP（Pak1-3' 非翻译区-6：rs31627325）强烈抑制皮肤肿瘤。此外，MBNL1 与 FVB-等位基因（6）结合更强，并通过多聚腺苷酸化调节 Pak1 的 3' 非翻译区的转录物长度和肿瘤发生。因此，Pak1 的可变多聚腺苷酸化由 rs31627325 顺式调节。
