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癌症中非规范 BAF 复合物的剪接体破坏。

Spliceosomal disruption of the non-canonical BAF complex in cancer.

机构信息

Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Department of Hematology-Oncology, Institute of Biomedical Research and Innovation, Foundation for Biomedical Research and Innovation at Kobe, Kobe, Japan.

出版信息

Nature. 2019 Oct;574(7778):432-436. doi: 10.1038/s41586-019-1646-9. Epub 2019 Oct 9.

DOI:10.1038/s41586-019-1646-9
PMID:31597964
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6858563/
Abstract

SF3B1 is the most commonly mutated RNA splicing factor in cancer, but the mechanisms by which SF3B1 mutations promote malignancy are poorly understood. Here we integrated pan-cancer splicing analyses with a positive-enrichment CRISPR screen to prioritize splicing alterations that promote tumorigenesis. We report that diverse SF3B1 mutations converge on repression of BRD9, which is a core component of the recently described non-canonical BAF chromatin-remodelling complex that also contains GLTSCR1 and GLTSCR1L. Mutant SF3B1 recognizes an aberrant, deep intronic branchpoint within BRD9 and thereby induces the inclusion of a poison exon that is derived from an endogenous retroviral element and subsequent degradation of BRD9 mRNA. Depletion of BRD9 causes the loss of non-canonical BAF at CTCF-associated loci and promotes melanomagenesis. BRD9 is a potent tumour suppressor in uveal melanoma, such that correcting mis-splicing of BRD9 in SF3B1-mutant cells using antisense oligonucleotides or CRISPR-directed mutagenesis suppresses tumour growth. Our results implicate the disruption of non-canonical BAF in the diverse cancer types that carry SF3B1 mutations and suggest a mechanism-based therapeutic approach for treating these malignancies.

摘要

SF3B1 是癌症中最常发生突变的 RNA 剪接因子，但 SF3B1 突变促进恶性肿瘤的机制仍不清楚。在这里，我们将泛癌症剪接分析与正向富集 CRISPR 筛选相结合，优先确定促进肿瘤发生的剪接改变。我们报告说，多种 SF3B1 突变都集中在抑制 BRD9 上，BRD9 是最近描述的非典型 BAF 染色质重塑复合物的核心组成部分，该复合物还包含 GLTSCR1 和 GLTSCR1L。突变的 SF3B1 识别 BRD9 中异常的深内含子分支点，从而诱导来自内源性逆转录病毒元件的毒性质子的包含，随后 BRD9 mRNA 降解。BRD9 的缺失会导致 CTCF 相关位点失去非典型 BAF，并促进黑色素瘤的发生。BRD9 是葡萄膜黑色素瘤中的一种有效的肿瘤抑制因子，因此，使用反义寡核苷酸或 CRISPR 指导的诱变纠正 SF3B1 突变细胞中 BRD9 的错误剪接，可以抑制肿瘤生长。我们的研究结果表明，非典型 BAF 的破坏与携带 SF3B1 突变的多种癌症类型有关，并为治疗这些恶性肿瘤提供了一种基于机制的治疗方法。

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