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Suppression of DDX39B sensitizes ovarian cancer cells to DNA-damaging chemotherapeutic agents via destabilizing BRCA1 mRNA

Oncogene volume 39, pages 7051–7062 (2020)Cite this article

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Abstract

Multiple RNA processing events including transcription, mRNA splicing, and export are delicately coordinated by the TREX complex. As one of the essential subunits, DDX39B couples the splicing and export machineries by recruiting ALYREF onto mRNA. In this study, we further explore the functions of DDX39B in handling damaged DNA, and unexpectedly find that DDX39B facilitates DNA repair by homologous recombination through upregulating BRCA1. Specifically, DDX39B binds to and stabilizes BRCA1 mRNA. DDX39B ensures ssDNA formation and RAD51 accumulation at DSB sites by maintaining BRCA1 levels. Without DDX39B being present, ovarian cancer cells exhibit hypersensitivity to DNA-damaging chemotherapeutic agents like platinum or PARPi. Moreover, DDX39B-deficient mice show embryonic lethality or developmental retardation, highly reminiscent of those lacking BRCA1. High DDX39B expression is correlated with worse survival in ovarian cancer patients. Thus, DDX39B suppression represents a rational approach for enhancing the efficacy of chemotherapy in BRCA1-proficient ovarian cancers.

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Fig. 1: DDX39B-deficient cells exhibit hypersensitivity to DNA-damaging agents.
Fig. 2: DDX39B facilitates ssDNA formation and RAD51 accumulation at DSBs.
Fig. 3: DDX39B affects damaged DNA repair through upregulating BRCA1.
Fig. 4: DDX39B associates with and stabilizes BRCA1 mRNA.
Fig. 5: The phenotypes of mice lacking DDX39B.
Fig. 6: DDX39B is a potential chemotherapeutic target for ovarian cancer treatment.

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Acknowledgements

We are grateful to members of the Wang laboratory for insightful discussions and technical assistance. This study was supported by grants from the National Key R&D Program of China (2017YFA0503900 and 2016YFC1302100), the National Natural Science Foundation of China (81672981, 81872282, 81903255, and 81972608), and Beijing Municipal Natural Science Foundation (7182082).

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Authors and Affiliations

  1. Department of Radiation Medicine, Institute of Systems Biomedicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China

    Zhanzhan Xu, Xiaoman Li, Hanxiao Li, Chen Nie, Wanchang Liu, Shiwei Li, Weibin Wang & Jiadong Wang

  2. Department of Medical Bioinformatics, Institute of Systems Biomedicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China

    Zelin Liu

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Xu, Z., Li, X., Li, H. et al. Suppression of DDX39B sensitizes ovarian cancer cells to DNA-damaging chemotherapeutic agents via destabilizing BRCA1 mRNA. Oncogene 39, 7051–7062 (2020). https://doi.org/10.1038/s41388-020-01482-x

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