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

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.
Mesh Terms:
Animals, Antineoplastic Agents, BRCA1 Protein, Cell Line, Tumor, DEAD-box RNA Helicases, DNA Breaks, Double-Stranded, DNA, Single-Stranded, Drug Resistance, Neoplasm, Female, Gene Expression Regulation, Neoplastic, Gene Knockdown Techniques, Humans, Mice, Mice, Knockout, Nuclear Proteins, Ovarian Neoplasms, Poly(ADP-ribose) Polymerase Inhibitors, RNA Splicing, RNA Stability, RNA, Messenger, RNA-Binding Proteins, Rad51 Recombinase, Recombinational DNA Repair, Survival Rate, Transcription Factors, Up-Regulation
Oncogene
Date: Dec. 01, 2019
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