RBM6 splicing factor promotes homologous recombination repair of double-strand breaks and modulates sensitivity to chemotherapeutic drugs.
Animals
Antineoplastic Agents
/ therapeutic use
Ataxia Telangiectasia Mutated Proteins
/ metabolism
Cell Line
Cisplatin
/ therapeutic use
DNA Breaks, Double-Stranded
Drug Resistance, Neoplasm
Female
HCT116 Cells
Homologous Recombination
Humans
MCF-7 Cells
Mammary Neoplasms, Experimental
/ drug therapy
Mice
Mice, SCID
Nerve Tissue Proteins
/ genetics
Nuclear Proteins
/ genetics
Poly(ADP-ribose) Polymerases
/ metabolism
RNA Stability
RNA-Binding Proteins
/ genetics
Triple Negative Breast Neoplasms
/ metabolism
Journal
Nucleic acids research
ISSN: 1362-4962
Titre abrégé: Nucleic Acids Res
Pays: England
ID NLM: 0411011
Informations de publication
Date de publication:
18 11 2021
18 11 2021
Historique:
accepted:
07
10
2021
revised:
26
09
2021
received:
17
02
2021
pubmed:
1
11
2021
medline:
28
12
2021
entrez:
31
10
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 34718714
pii: 6413602
doi: 10.1093/nar/gkab976
pmc: PMC8599755
doi:
Substances chimiques
APBB1 protein, human
0
Antineoplastic Agents
0
Nerve Tissue Proteins
0
Nuclear Proteins
0
RBM6 protein, human
0
RNA-Binding Proteins
0
Poly(ADP-ribose) Polymerases
EC 2.4.2.30
ATM protein, human
EC 2.7.11.1
Ataxia Telangiectasia Mutated Proteins
EC 2.7.11.1
Cisplatin
Q20Q21Q62J
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
11708-11727Informations de copyright
© The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.
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