Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Department of Biological Chemistry, School of Medicine, University of California, Irvine, Irvine, CA 92697, USA; Division of Biostatistics, Dan L. Duncan Cancer Center and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Mol Cell. 2020 Mar 19;77(6):1206-1221.e7. doi: 10.1016/j.molcel.2019.12.022. Epub 2020 Jan 21.
Alternative polyadenylation (APA) contributes to transcriptome complexity by generating mRNA isoforms with varying 3' UTR lengths. APA leading to 3' UTR shortening (3' US) is a common feature of most cancer cells; however, the molecular mechanisms are not understood. Here, we describe a widespread mechanism promoting 3' US in cancer through ubiquitination of the mRNA 3' end processing complex protein, PCF11, by the cancer-specific MAGE-A11-HUWE1 ubiquitin ligase. MAGE-A11 is normally expressed only in the male germline but is frequently re-activated in cancers. MAGE-A11 is necessary for cancer cell viability and is sufficient to drive tumorigenesis. Screening for targets of MAGE-A11 revealed that it ubiquitinates PCF11, resulting in loss of CFIm25 from the mRNA 3' end processing complex. This leads to APA of many transcripts affecting core oncogenic and tumor suppressors, including cyclin D2 and PTEN. These findings provide insights into the molecular mechanisms driving APA in cancer and suggest therapeutic strategies.
可变多聚腺苷酸化（APA）通过产生具有不同 3'UTR 长度的 mRNA 异构体，为转录组的复杂性做出贡献。导致 3'UTR 缩短（3'US）的 APA 是大多数癌细胞的一个常见特征；然而，其分子机制尚不清楚。在这里，我们描述了一种通过癌症特异性 MAGE-A11-HUWE1 泛素连接酶对 mRNA 3' 端加工复合物蛋白 PCF11 的泛素化，促进癌症中 3'US 的广泛机制。MAGE-A11 通常仅在男性生殖细胞中表达，但在癌症中经常被重新激活。MAGE-A11 是癌细胞存活所必需的，足以驱动肿瘤发生。对 MAGE-A11 的靶标进行筛选表明，它泛素化 PCF11，导致 CFIm25 从 mRNA 3' 端加工复合物中丢失。这导致许多转录物的 APA 发生，影响核心致癌基因和肿瘤抑制基因，包括细胞周期蛋白 D2 和 PTEN。这些发现为驱动癌症中 APA 的分子机制提供了深入了解，并提出了治疗策略。
