RBM6 splicing factor promotes homologous recombination repair of double-strand breaks and modulates sensitivity to chemotherapeutic drugs
| Autor: | Laila A. Bishara, Samah W. Awwad, Feras E. Machour, Tirza Bidany-Mizrahi, Nabieh Ayoub, Enas R Abu-Zhayia, Stefan Meinke, Rami I. Aqeilan, Florian Heyd |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
AcademicSubjects/SCI00010
RNA Stability Antineoplastic Agents Nerve Tissue Proteins Triple Negative Breast Neoplasms Ataxia Telangiectasia Mutated Proteins Mice SCID Biology Genome Integrity Repair and Replication medicine.disease_cause homologous recombination repair Cell Line 03 medical and health sciences Splicing factor Mice 0302 clinical medicine Genetics medicine Animals Humans DNA Breaks Double-Stranded Homologous Recombination 030304 developmental biology 0303 health sciences Gene knockdown Alternative splicing Cancer Mammary Neoplasms Experimental Nuclear Proteins RNA-Binding Proteins medicine.disease HCT116 Cells 3. Good health splicing factor Drug Resistance Neoplasm 030220 oncology & carcinogenesis Cancer cell RNA splicing Cancer research MCF-7 Cells Female RBM6 Cisplatin Poly(ADP-ribose) Polymerases Homologous recombination Carcinogenesis |
| Zdroj: | Nucleic Acids Research Nucleic Acid Research |
| ISSN: | 1362-4962 0305-1048 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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