生物
RNA剪接
同源重组
基因敲除
癌变
顺铂
RNA结合蛋白
癌症研究
DNA修复
拼接因子
调节器
核糖核酸
细胞生物学
合成致死
分子生物学
DNA
癌症
遗传学
基因
化疗
作者
Feras E. Machour,Enas R Abu-Zhayia,Samah W. Awwad,Tirza Bidany-Mizrahi,Stefan Meinke,Laila A. Bishara,Florian Heyd,Rami I. Aqeilan,Nabieh Ayoub
摘要
RNA-binding proteins regulate mRNA processing and translation and are often aberrantly expressed in cancer. The RNA-binding motif protein 6, RBM6, is a known alternative splicing factor that harbors tumor suppressor activity and is frequently mutated in human cancer. Here, we identify RBM6 as a novel regulator of homologous recombination (HR) repair of DNA double-strand breaks (DSBs). Mechanistically, we show that RBM6 regulates alternative splicing-coupled nonstop-decay of a positive HR regulator, Fe65/APBB1. RBM6 knockdown leads to a severe reduction in Fe65 protein levels and consequently impairs HR of DSBs. Accordingly, RBM6-deficient cancer cells are vulnerable to ATM and PARP inhibition and show remarkable sensitivity to cisplatin. Concordantly, cisplatin administration inhibits the growth of breast tumor devoid of RBM6 in mouse xenograft model. Furthermore, we observe that RBM6 protein is significantly lost in metastatic breast tumors compared with primary tumors, thus suggesting RBM6 as a potential therapeutic target of advanced breast cancer. Collectively, our results elucidate the link between the multifaceted roles of RBM6 in regulating alternative splicing and HR of DSBs that may contribute to tumorigenesis, and pave the way for new avenues of therapy for RBM6-deficient tumors.
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