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 DD...

Ausführliche Beschreibung

Gespeichert in:

Bibliographische Detailangaben
Veröffentlicht in:	Oncogene 2020-11, Vol.39 (47), p.7051-7062
Hauptverfasser:	Xu, Zhanzhan, Li, Xiaoman, Li, Hanxiao, Nie, Chen, Liu, Wanchang, Li, Shiwei, Liu, Zelin, Wang, Weibin, Wang, Jiadong
Format:	Artikel
Sprache:	eng
Schlagworte:	13/1 13/106 13/109 13/89 14/19 38/91 631/337/1427/2190 631/67 64/60 82/29 82/58 82/80 82/83 Animals Antineoplastic Agents - pharmacology Antineoplastic Agents - therapeutic use Apoptosis BRCA1 protein BRCA1 Protein - genetics BRCA1 Protein - metabolism Cancer Care and treatment Cell Biology Cell Line, Tumor Chemotherapy Complications and side effects DEAD-box RNA Helicases - antagonists & inhibitors DEAD-box RNA Helicases - genetics DEAD-box RNA Helicases - metabolism Deoxyribonucleic acid DNA DNA Breaks, Double-Stranded - drug effects DNA damage DNA repair DNA, Single-Stranded - metabolism Drug Resistance, Neoplasm - drug effects Drug Resistance, Neoplasm - genetics Embryos Female Gene Expression Regulation, Neoplastic - drug effects Gene Knockdown Techniques Genetic aspects Health aspects Homologous recombination Human Genetics Humans Hypersensitivity Internal Medicine Lethality Medicine Medicine & Public Health Messenger RNA Methods Mice Mice, Knockout Nuclear Proteins - metabolism Oncology Oncology, Experimental Ovarian cancer Ovarian Neoplasms - drug therapy Ovarian Neoplasms - genetics Ovarian Neoplasms - mortality Ovarian Neoplasms - pathology Platinum Poly(ADP-ribose) Polymerase Inhibitors - pharmacology Poly(ADP-ribose) Polymerase Inhibitors - therapeutic use Rad51 Recombinase - metabolism Recombinational DNA Repair - drug effects RNA processing RNA Splicing - drug effects RNA Stability - drug effects RNA, Messenger - metabolism RNA-Binding Proteins - metabolism Survival Rate Transcription Transcription Factors - metabolism Up-Regulation
Online-Zugang:	Volltext
Tags:	Tag hinzufügen Keine Tags, Fügen Sie den ersten Tag hinzu!

Beschreibung
Zusammenfassung:	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.
ISSN:	0950-9232 1476-5594
DOI:	10.1038/s41388-020-01482-x