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CircHIPK3 and FMRP compete for direct binding to BRCA1 mRNA controlling its protein levels and DNA damage response

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE246226 | GEO | 2024/09/13

REPOSITORIES: GEO

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CircHIPK3 and FMRP compete for direct binding to BRCA1 mRNA controlling its protein levels and DNA damage response [miRNA_pulldown]

Project description:Circular RNAs (circRNAs) are covalently closed RNA molecules widely expressed in eukaryotes and regulated in several pathological processes, including cancer. Many studies point to their mechanism of action as miRNA and protein sponges; however, we propose a new functionality based on circRNA-mRNA interaction to regulate mRNA fate. We show that the widely expressed circHIPK3 directly interacts in vivo with the BRCA1 mRNA through the back-splicing region. This interaction favoured the translation of BRCA1 by competing for the binding of the FMRP1 RNA-binding protein, which acts as a repressor of BRCA1 translation. CircHIPK3 depletion or disruption of the CircRNA-mRNA interaction decreased BRCA1 levels and increased DNA damage, sensitizing several cancer cell lines to DNA-damage-inducing agents and rendering them susceptible to synthetic lethality. Additionally, mimicking circHIPK3 interaction with lock-nucleic acid (LNA) oligonucleotides restores BRCA1 levels in hereditary breast cancer model cells, underscoring circRNA-mRNA interaction’s importance in regulating cell homeostasis and drug response.

2024-09-13 | GSE246225 | GEO

CircHIPK3 and FMRP compete for direct binding to BRCA1 mRNA controlling its protein levels and DNA damage response [RNA_pulldown]

2024-09-13 | GSE246224 | GEO

CircHIPK3 and FMRP compete for direct binding to BRCA1 mRNA controlling its protein levels and DNA damage response

Project description:CircHIPK3 and FMRP compete for direct binding to BRCA1 mRNA controlling its protein levels and DNA damage response

| PRJNA1032074 | ENA

CircHIPK3 and FMRP compete for direct binding to BRCA1 mRNA controlling its protein levels and DNA damage response [RNA_pulldown]

Project description:CircHIPK3 and FMRP compete for direct binding to BRCA1 mRNA controlling its protein levels and DNA damage response [RNA_pulldown]

| PRJNA1032103 | ENA

CircHIPK3 and FMRP compete for direct binding to BRCA1 mRNA controlling its protein levels and DNA damage response [miRNA_pulldown]

Project description:CircHIPK3 and FMRP compete for direct binding to BRCA1 mRNA controlling its protein levels and DNA damage response [miRNA_pulldown]

| PRJNA1032102 | ENA

NUSAP1 influences the DNA damage response by controlling BRCA1 protein levels.

Project description:NUSAP1 has been reported to function in mitotic spindle assembly, chromosome segregation, and regulation of cytokinesis. In this study, we find that NUSAP1 has hitherto unknown functions in the key BRCA1-regulated pathways of double strand DNA break repair and centrosome duplication. Both these pathways are important for maintenance of genomic stability, and any defects in these pathways can cause tumorigenesis. Depletion of NUSAP1 from cells led to the suppression of double strand DNA break repair via the homologous recombination and single-strand annealing pathways. The presence of NUSAP1 was also found to be important for the control of centrosome numbers. We have found evidence that NUSAP1 plays a role in these processes through regulation of BRCA1 protein levels, and BRCA1 overexpression from a plasmid mitigates the defective phenotypes seen upon NUSAP1 depletion. We found that after NUSAP1 depletion there is a decrease in BRCA1 recruitment to ionizing radiation-induced foci. Results from this study reveal a novel association between BRCA1 and NUSAP1 and suggests a mechanism whereby NUSAP1 is involved in carcinogenesis.

| S-EPMC4026076 | biostudies-literature

FMRP, a multifunctional RNA-binding protein in quest of a new identity.

Project description: Not available

| S-EPMC9399724 | biostudies-literature

Identification of consensus binding sites clarifies FMRP binding determinants.

Project description:Fragile X mental retardation protein (FMRP) is a multifunctional RNA-binding protein with crucial roles in neuronal development and function. Efforts aimed at elucidating how FMRP target mRNAs are selected have produced divergent sets of target mRNA and putative FMRP-bound motifs, and a clear understanding of FMRP's binding determinants has been lacking. To clarify FMRP's binding to its target mRNAs, we produced a shared dataset of FMRP consensus binding sequences (FCBS), which were reproducibly identified in two published FMRP CLIP sequencing datasets. This comparative dataset revealed that of the various sequence and structural motifs that have been proposed to specify FMRP binding, the short sequence motifs TGGA and GAC were corroborated, and a novel TAY motif was identified. In addition, the distribution of the FCBS set demonstrates that FMRP preferentially binds to the coding region of its targets but also revealed binding along 3' UTRs in a subset of target mRNAs. Beyond probing these putative motifs, the FCBS dataset of reproducibly identified FMRP binding sites is a valuable tool for investigating FMRP targets and function.

| S-EPMC5001617 | biostudies-literature

HCV NS5A and IRF9 compete for CypA binding.

Project description:Background & aimsCyclophilin A (CypA) is vital for HCV replication. Cyp inhibitors successfully decrease viral loads in HCV-infected patients. However, their mechanisms of action remain unknown. Since interferon (IFN) can also suppress HCV replication, we asked whether a link between CypA and the IFN response exists.MethodsWe used cellular and recombinant pulldown approaches to investigate the possibility of a specific association of CypA with host ligands.ResultsWe found for the first time that CypA binds to a major component of the IFN response - the IFN regulatory factor 9 (IRF9). IRF9 is the DNA-binding component of the transcriptional IFN-stimulated gene factor 3 (ISGF3). CypA binds directly to IRF9 via its peptidyl-prolyl isomerase (PPIase) pocket. Cyp inhibitors such as cyclosporine A (CsA) or non-immunosuppressive derivates such as alisporivir and SCY-635, prevent IRF9-CypA complex formation. CypA binds to the C-terminal IRF-association-domain (IAD), but not to the DNA-binding or linker domains of IRF9. Remarkably, CypA associates with the multimeric ISGF3 complex. We also obtained evidence that CypA neutralization enhances IFN-induced transcription. Interestingly, the hepatitis C virus (HCV) non-structural 5A (NS5A) protein, which is known to modulate the IFN response, competes with IRF9 for CypA binding and can prevent the formation of IRF9-CypA complexes.ConclusionsThis study demonstrates for the first time that CypA binds specifically to a component of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway, IRF9. This study also reveals a novel opportunity of HCV to modulate the IFN response via NS5A.

| S-EPMC3527675 | biostudies-literature

A chromatin-dependent role of the fragile X mental retardation protein FMRP in the DNA damage response.

Project description:Fragile X syndrome, a common form of inherited intellectual disability, is caused by loss of the fragile X mental retardation protein FMRP. FMRP is present predominantly in the cytoplasm, where it regulates translation of proteins that are important for synaptic function. We identify FMRP as a chromatin-binding protein that functions in the DNA damage response (DDR). Specifically, we show that FMRP binds chromatin through its tandem Tudor (Agenet) domain in vitro and associates with chromatin in vivo. We also demonstrate that FMRP participates in the DDR in a chromatin-binding-dependent manner. The DDR machinery is known to play important roles in developmental processes such as gametogenesis. We show that FMRP occupies meiotic chromosomes and regulates the dynamics of the DDR machinery during mouse spermatogenesis. These findings suggest that nuclear FMRP regulates genomic stability at the chromatin interface and may impact gametogenesis and some developmental aspects of fragile X syndrome.

| S-EPMC4038154 | biostudies-literature

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