Article (Scientific journals)
The transcription factor c-Jun inhibits RBM39 to reprogram pre-mRNA splicing during genotoxic stress.
Lemaitre, Florence; Chakrama, Fatima; O'Grady, Tina et al.
2022In Nucleic Acids Research, 50 (22), p. 12768 - 12789
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Keywords :
RNA Precursors; Cisplatin; RNA-Binding Proteins; Nuclear Proteins; Transcription Factors; RNA-Binding Proteins/genetics; RNA-Binding Proteins/metabolism; Nuclear Proteins/metabolism; Alternative Splicing/genetics; DNA Damage; Transcription Factors/metabolism; RNA Precursors/genetics; RNA Precursors/metabolism; Cisplatin/pharmacology; Cisplatin/metabolism; Genetics
Abstract :
[en] Genotoxic agents, that are used in cancer therapy, elicit the reprogramming of the transcriptome of cancer cells. These changes reflect the cellular response to stress and underlie some of the mechanisms leading to drug resistance. Here, we profiled genome-wide changes in pre-mRNA splicing induced by cisplatin in breast cancer cells. Among the set of cisplatin-induced alternative splicing events we focused on COASY, a gene encoding a mitochondrial enzyme involved in coenzyme A biosynthesis. Treatment with cisplatin induces the production of a short isoform of COASY lacking exons 4 and 5, whose depletion impedes mitochondrial function and decreases sensitivity to cisplatin. We identified RBM39 as a major effector of the cisplatin-induced effect on COASY splicing. RBM39 also controls a genome-wide set of alternative splicing events partially overlapping with the cisplatin-mediated ones. Unexpectedly, inactivation of RBM39 in response to cisplatin involves its interaction with the AP-1 family transcription factor c-Jun that prevents RBM39 binding to pre-mRNA. Our findings therefore uncover a novel cisplatin-induced interaction between a splicing regulator and a transcription factor that has a global impact on alternative splicing and contributes to drug resistance.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Lemaitre, Florence  ;  Université de Liège - ULiège > GIGA
Chakrama, Fatima  ;  Université de Liège - ULiège > GIGA > GIGA I3 - Virology and Immunology
O'Grady, Tina  ;  Université de Liège - ULiège > GIGA > GIGA Molecular Biology of Diseases - Gene Expression & Cancer
Peulen, Olivier  ;  Université de Liège - ULiège > GIGA > GIGA Cancer - Metastases Research Laboratory
Rademaker, Gilles  ;  Université de Liège - ULiège > GIGA > GIGA Cancer - Metastases Research Laboratory
Deward, Adeline ;  Université de Liège - ULiège > Département de gestion vétérinaire des Ressources Animales (DRA) > Génomique animale
Chabot, Benoit ;  Department of Microbiology and Infectious Diseases, Faculty of Medicine and Health Sciences. Université de Sherbrooke, Sherbrooke, Québec, Canada
Piette, Jacques ;  Université de Liège - ULiège > GIGA > GIGA I3 - Virology and Immunology
Colige, Alain ;  Université de Liège - ULiège > GIGA > GIGA Cancer - Connective Tissue Biology
Lambert, Charles ;  Université de Liège - ULiège > GIGA > GIGA Cancer - Connective Tissue Biology
Dequiedt, Franck   ;  Université de Liège - ULiège > Département des sciences de la vie > Génétique et biologie moléculaires animales
Habraken, Yvette   ;  Université de Liège - ULiège > Département des sciences de la vie
 These authors have contributed equally to this work.
Language :
English
Title :
The transcription factor c-Jun inhibits RBM39 to reprogram pre-mRNA splicing during genotoxic stress.
Alternative titles :
[fr] Le facteur de transcription c-Jun inhibe RBM39 pour reprogrammer l'épissage des ARNs pré-messager lors d'un stress génotoxique
Publication date :
09 December 2022
Journal title :
Nucleic Acids Research
ISSN :
0305-1048
eISSN :
1362-4962
Publisher :
Oxford University Press (OUP), England
Volume :
50
Issue :
22
Pages :
12768 - 12789
Peer reviewed :
Peer Reviewed verified by ORBi
Funders :
ULiège - Université de Liège [BE]
CAC - Centre anticancéreux près l'Université de Liège asbl [BE]
Fonds Léon Fredericq [BE]
BELSPO - Belgian Science Policy Office [BE]
Belgian Foundation Against Cancer [BE]
CIHR - Canadian Institutes of Health Research [CA]
Télévie [BE]
F.R.S.-FNRS - Fonds de la Recherche Scientifique [BE]
Funding number :
BelPD
Funding text :
Fonds Sectoriels de l'Université de Liège; Actions de Recherche Concertée
Commentary :
The authors wish it to be known that, in their opinion, the first two authors and last two authors should be regarded as Joint First and Joint Last Authors,respectively
Available on ORBi :
since 10 January 2023

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