Bak-Gordon Pedro, Manley James L
Department of Biological Sciences, Columbia University, New York, New York 10027, USA.
Department of Biological Sciences, Columbia University, New York, New York 10027, USA
RNA. 2025 Feb 19;31(3):314-332. doi: 10.1261/rna.080368.124.
Highly recurrent somatic mutations in the gene encoding the core splicing factor SF3B1 are drivers of multiple cancer types. SF3B1 is a scaffold protein that orchestrates multivalent protein-protein interactions within the spliceosome that are essential for recognizing the branchsite (BS) and selecting the 3' splice site during the earliest stage of pre-mRNA splicing. In this review, we first describe the molecular mechanism by which multiple oncogenic mutations disrupt splicing. This involves perturbation of an early spliceosomal trimeric protein complex necessary for accurate BS recognition in a subset of introns, which leads to activation of upstream branchpoints and selection of cryptic 3' splice sites. We next discuss how specific transcripts affected by aberrant splicing in -mutant cells contribute to the initiation and progression of cancer. Finally, we highlight the prognostic value and disease phenotypes of different cancer-associated mutations, which is critical for developing new targeted therapeutics against -mutant cancers still lacking in the clinic.
编码核心剪接因子SF3B1的基因中高度复发的体细胞突变是多种癌症类型的驱动因素。SF3B1是一种支架蛋白，它协调剪接体内的多价蛋白质-蛋白质相互作用，这些相互作用对于在前体mRNA剪接的最早阶段识别分支位点（BS）和选择3'剪接位点至关重要。在本综述中，我们首先描述多种致癌突变破坏剪接的分子机制。这涉及扰乱在一部分内含子中准确识别BS所需的早期剪接体三聚体蛋白复合物，从而导致上游分支点的激活和隐蔽3'剪接位点的选择。接下来，我们讨论突变细胞中受异常剪接影响的特定转录本如何促进癌症的发生和发展。最后，我们强调不同癌症相关突变的预后价值和疾病表型，这对于开发针对临床上仍缺乏的突变癌症的新靶向治疗方法至关重要。
