Cancer-Associated SF3B1 Mutations Confer a BRCA-Like Cellular Phenotype and Synthetic Lethality to PARP Inhibitors.
Cancer-Associated SF3B1 Mutations Confer a BRCA-Like Cellular Phenotype and Synthetic Lethality to PARP Inhibitors.
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DOI：
10.1158/0008-5472.can-21-1843
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发表时间：
2022-03-01
期刊：
影响因子：
11.2
通讯作者：
Savage KI
中科院分区：
文献类型：
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作者：
Lappin KM;Barros EM;Jhujh SS;Irwin GW;McMillan H;Liberante FG;Latimer C;La Bonte MJ;Mills KI;Harkin DP;Stewart GS;Savage KI
与癌症相关的 SF3B1K700E 突变通过产生基因毒性 R 环和停滞的复制叉、有缺陷的同源重组以及增加的复制叉降解来诱导 DNA 损伤，这些可以用 PARP 抑制剂来靶向。 SF3B1 突变已在多种癌症类型中被发现。这一关键的剪接体成分促进了数千个基因的有效 mRNA 剪接，其中包括那些在细胞对 DNA 损伤的反应中起关键作用的基因。在这里，我们证明 SF3B1 的耗尽会特别损害同源重组 (HR)，并且随着 BRCA1 的丢失而上位。更重要的是，SF3B1 中最常见的癌症相关突变 K700E 也会影响 HR 效率，从而增加细胞对电离辐射和各种化疗药物（包括 PARP 抑制剂）的敏感性。此外，SF3B1 K700E 突变诱导非计划的 R 环形成、复制叉停滞、复制叉降解增加以及有缺陷的复制叉重新启动。总而言之，这些数据表明，SF3B1 中的肿瘤相关突变会诱导类似 BRCA 的细胞表型，从而赋予 DNA 损伤剂和 PARP 抑制剂合成致死性，可用于治疗。与癌症相关的 SF3B1K700E 突变通过产生基因毒性 R 环和停滞的复制叉、有缺陷的同源重组以及增加的复制叉降解来诱导 DNA 损伤，这些可以用 PARP 抑制剂来靶向。
The cancer-associated SF3B1K700E mutation induces DNA damage via generation of genotoxic R-loops and stalled replication forks, defective homologous recombination, and increased replication fork degradation, which can be targeted with PARP inhibitors. Mutations in SF3B1 have been identified across several cancer types. This key spliceosome component promotes the efficient mRNA splicing of thousands of genes including those with crucial roles in the cellular response to DNA damage. Here, we demonstrate that depletion of SF3B1 specifically compromises homologous recombination (HR) and is epistatic with loss of BRCA1. More importantly, the most prevalent cancer-associated mutation in SF3B1, K700E, also affects HR efficiency and as a consequence, increases the cellular sensitivity to ionizing radiation and a variety of chemotherapeutic agents, including PARP inhibitors. In addition, the SF3B1 K700E mutation induced unscheduled R-loop formation, replication fork stalling, increased fork degradation, and defective replication fork restart. Taken together, these data suggest that tumor-associated mutations in SF3B1 induce a BRCA-like cellular phenotype that confers synthetic lethality to DNA-damaging agents and PARP inhibitors, which can be exploited therapeutically. The cancer-associated SF3B1K700E mutation induces DNA damage via generation of genotoxic R-loops and stalled replication forks, defective homologous recombination, and increased replication fork degradation, which can be targeted with PARP inhibitors.