Abstract
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.
Highlights
Defective DNA damage repair leads to genomic instability, which is considered a common characteristic of cancer cells
Since many tumor suppressor genes play a role in DNA repair, and since RBM6 is phosphorylated in response to DNA damage including ionizing radiation (IR) [63,64,65], we were prompted to investigate whether RBM6 is involved in double-strand breaks (DSBs) repair
To address whether ␥ H2AX levels in RBM6-deficient cells are elevated after exogenous DNA damage, MCF10ARBM6-KO1 and MCF10AshRBM6#1 cells were exposed to IR, followed by ␥ H2AX quantification at the indicated timepoints after IR exposure
Summary
Defective DNA damage repair leads to genomic instability, which is considered a common characteristic of cancer cells. Splicing factors were shown to accumulate at DNA damage sites, suggesting that they may play a direct role in DDR beside their canonical function in pre-mRNA splicing [17,24,25,26,27,28]. Depletion of some SFs leads to abnormal splicing of DDR genes, disrupting the integrity of DNA damage repair and sensitizing cells to genotoxic agents [16,29,31]. The splicing machinery provides a basis for innovative-splicing-targeted cancer therapies [24,33,34,35,36,37]
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