Our official English website, www.x-mol.net, welcomes your
feedback! (Note: you will need to create a separate account there.)
A Cancer-Specific Ubiquitin Ligase Drives mRNA Alternative Polyadenylation by Ubiquitinating the mRNA 3' End Processing Complex.
Molecular Cell ( IF 14.5 ) Pub Date : 2020-01-08 , DOI: 10.1016/j.molcel.2019.12.022 Seung Wook Yang 1 , Lei Li 2 , Jon P Connelly 1 , Shaina N Porter 1 , Kiran Kodali 3 , Haiyun Gan 1 , Jung Mi Park 1 , Klementina Fon Tacer 1 , Heather Tillman 4 , Junmin Peng 3 , Shondra M Pruett-Miller 1 , Wei Li 2 , Patrick Ryan Potts 1
Molecular Cell ( IF 14.5 ) Pub Date : 2020-01-08 , DOI: 10.1016/j.molcel.2019.12.022 Seung Wook Yang 1 , Lei Li 2 , Jon P Connelly 1 , Shaina N Porter 1 , Kiran Kodali 3 , Haiyun Gan 1 , Jung Mi Park 1 , Klementina Fon Tacer 1 , Heather Tillman 4 , Junmin Peng 3 , Shondra M Pruett-Miller 1 , Wei Li 2 , Patrick Ryan Potts 1
Affiliation
|
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.
中文翻译：
癌症特异性泛素连接酶通过泛素化mRNA 3'末端加工复合物来驱动mRNA替代性聚腺苷酸化。
备选的聚腺苷酸化（APA）通过产生具有不同3'UTR长度的mRNA同工型来增加转录组的复杂性。APA导致3'UTR缩短（3'US）是大多数癌细胞的共同特征。但是，分子机制尚不清楚。在这里，我们描述了一种广泛的机制，可通过癌症特异性MAGE-A11-HUWE1泛素连接酶使mRNA 3'末端加工复合蛋白PCF11泛素化来促进癌症中的3'US。MAGE-A11通常仅在雄性种系中表达，但在癌症中经常重新激活。MAGE-A11对于癌细胞生存力是必需的，并且足以驱动肿瘤发生。对MAGE-A11靶标的筛选显示，它可泛素化PCF11，导致CFIm25从mRNA 3'末端加工复合物中丢失。这会导致许多转录物的APA影响核心致癌物和肿瘤抑制物，包括细胞周期蛋白D2和PTEN。这些发现为深入了解驱动APA在癌症中的分子机制提供了见识，并提出了治疗策略。
更新日期：2020-01-22
中文翻译：
癌症特异性泛素连接酶通过泛素化mRNA 3'末端加工复合物来驱动mRNA替代性聚腺苷酸化。
备选的聚腺苷酸化（APA）通过产生具有不同3'UTR长度的mRNA同工型来增加转录组的复杂性。APA导致3'UTR缩短（3'US）是大多数癌细胞的共同特征。但是，分子机制尚不清楚。在这里，我们描述了一种广泛的机制，可通过癌症特异性MAGE-A11-HUWE1泛素连接酶使mRNA 3'末端加工复合蛋白PCF11泛素化来促进癌症中的3'US。MAGE-A11通常仅在雄性种系中表达，但在癌症中经常重新激活。MAGE-A11对于癌细胞生存力是必需的，并且足以驱动肿瘤发生。对MAGE-A11靶标的筛选显示，它可泛素化PCF11，导致CFIm25从mRNA 3'末端加工复合物中丢失。这会导致许多转录物的APA影响核心致癌物和肿瘤抑制物，包括细胞周期蛋白D2和PTEN。这些发现为深入了解驱动APA在癌症中的分子机制提供了见识，并提出了治疗策略。
京公网安备 11010802027423号