We reported previously that a 2' fluoro-modified (2' F) phosphorothioate (PS) antisense oligonucleotides (ASOs) with 5-10-5 gapmer configuration interacted with proteins from Drosophila behavior/human splicing (DBHS) family with higher affinity than PS-ASOs modified with 2'-O-(2-methoxyethyl) (2' MOE) or 2',4'-constrained 2'-O-ethyl (cEt) did. Rapid degradation of these proteins and cytotoxicity were observed in cells treated with 2' F PS-ASO. Here, we report that 2' F gapmer PS-ASOs of different sequences caused reduction in levels of DBHS proteins and hepatotoxicity in mice. 2' F PS-ASOs induced activation of the P53 pathway and downregulation of metabolic pathways. Altered levels of RNA and protein markers for hepatotoxicity, liver necrosis, and apoptosis were observed as early as 24 to 48 hours after a single administration of the 2' F PS-ASO. The observed effects were not likely due to the hybridization-dependent RNase H1 cleavage of on- or potential off-target RNAs, or due to potential toxicity of 2' F nucleoside metabolites. Instead, we found that 2' F PS-ASO associated with more intra-cellular proteins including proteins from DBHS family. Our results suggest that protein-binding correlates positively with the 2' F modification-dependent loss of DBHS proteins and the toxicity of gapmer 2' F PS-ASO in vivo.
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http://dx.doi.org/10.1093/nar/gky060 | DOI Listing |
Eur J Med Genet
December 2024
CHU Lille, Institut de Génétique Médicale, F-59000 Lille, France; Univ. Lille, ULR7364 - RADEME - Maladies RAres du DEveloppement embryonnaire et du Métabolisme, F-59000 Lille, France. Electronic address:
The X-linked NONO gene encodes Non-Pou Domain-Containing Octamer-Binding Protein, a multifunctional member of the DBHS family involved in transcriptional regulation, RNA splicing and DNA repair. Pathogenic variants in NONO cause Intellectual Developmental Disorder, X-linked Syndromic (MIM #300967), characterised by intellectual disability, neurodevelopmental delay, cardiomyopathy, such as left ventricular non-compaction (LVNC), and congenital heart defects such as including atrial septal defect (ASD), ventricular septal defect (VSD), patent ductus arteriosus (PDA), and patent foramen ovale (PFO). This study reports three new patients with pathogenic hemizygous frameshift variants in NONO identified with exome sequencing, broadening the clinical presentation.
View Article and Find Full Text PDFNucleic Acids Res
December 2024
School of Molecular Sciences, The University of Western Australia, 35 Stirling Highway, Crawley, Western Australia 6009, Australia.
The proteins SFPQ (splicing Factor Proline/Glutamine rich) and NONO (non-POU domain-containing octamer-binding protein) are mammalian members of the Drosophila Behaviour/Human Splicing (DBHS) protein family, which share 76% sequence identity in their conserved 320 amino acid DBHS domain. SFPQ and NONO are involved in all steps of post-transcriptional regulation and are primarily located in mammalian paraspeckles: liquid phase-separated, ribonucleoprotein sub-nuclear bodies templated by NEAT1 long non-coding RNA. A combination of structured and low-complexity regions provide polyvalent interaction interfaces that facilitate homo- and heterodimerisation, polymerisation, interactions with oligonucleotides, mRNA, long non-coding RNA, and liquid phase-separation, all of which have been implicated in cellular homeostasis and neurological diseases including neuroblastoma.
View Article and Find Full Text PDFGenes Dev
November 2024
Division of Molecular, Cellular, and Developmental Biology, University of Dundee, Dundee DD1 5EH, United Kingdom;
The link between DNA methylation and neurodevelopmental disorders is well established. However, how DNA methylation is fine-tuned-ensuring precise gene expression and developmental fidelity-remains poorly understood. PROSER1, a known TET2 interactor, was recently linked to a severe neurodevelopmental disorder.
View Article and Find Full Text PDFPLoS Pathog
October 2024
Shandong Key Laboratory of Animal Disease Control and Breeding/Key Laboratory of Livestock and Poultry Multi-omics of MARA, Institute of Animal Science and Veterinary Medicine, Shandong Academy of Agricultural Sciences, Jinan, Shandong, China.
Biomed Pharmacother
November 2024
School of Pharmacy and Pharmaceutical Sciences & Institute of Materia Medica, Shandong First Medical University & Shandong Academy of Medical Sciences, NHC Key Laboratory of Biotechnology Drugs (Shandong Academy of Medical Sciences), Key Lab for Rare & Uncommon Diseases of Shandong Province, Jinan, Shandong 250117, China. Electronic address:
The Polypyrimidine Tract-Binding Protein-Associated Splicing Factor (PSF), a component of the Drosophila Behavior/Human Splicing (DBHS) complex, plays a pivotal role in cancer pathogenesis. The epigenetic regulation mediated by PSF and long noncoding RNA (lncRNA), along with PSF's alternative splicing activity, has been implicated in promoting cancer cell proliferation, migration, invasion, metastasis, and drug resistance in various human cancers. Recent research highlights the therapeutic promise of targeting the PSF-lncRNA interaction to combat aggressive malignancies, making it a compelling target for cancer therapy.
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