Functional roles of human Up-frameshift suppressor 3 (UPF3) proteins: From nonsense-mediated mRNA decay to neurodevelopmental disorders

Deka, Bhagyashree; Chandra, Pratap; Singh, Kusum

doi:10.1016/j.biochi.2020.10.011

Cited by 12 publications

(14 citation statements)

References 108 publications

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“…Interestingly, we found that HOTAIR might bind to UPF1. UPF1 is involved in a highly conserved RNA degradation pathway called nonsense-mediated RNA decay (NMD), which can lead to the degradation of mRNAs ( Alzahrani et al., 2020 ; Deka et al., 2020 ). Based on the above information, we hypothesized that HOTAIR might mediate the progression of ICH by binding to UPF1.…”

Section: Introductionmentioning

confidence: 99%

Paeonol inhibits the progression of intracerebral haemorrhage by mediating the HOTAIR/UPF1/ACSL4 axis

et al. 2021

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Intracerebral haemorrhage (ICH) is a devastating subtype of stroke with high morbidity and mortality. It has been reported that paeonol (PAN) inhibits the progression of ICH. However, the mechanism by which paeonol mediates the progression of ICH remains unclear. To mimic ICH in vitro, neuronal cells were treated with hemin. An in vivo model of ICH was established to detect the effect of paeonol on ferroptosis in neurons during ICH. Cell viability was tested by MTT assay. Furthermore, cell injury was detected by GSH, MDA and ROS assays. Ferroptosis was examined by iron assay. RT-qPCR and western blotting were used to detect gene and protein expression, respectively. The correlation among HOTAIR, UPF1 and ACSL4 was explored by FISH, RNA pull-down and RIP assays. Paeonol significantly inhibited the ferroptosis of neurons in ICH mice. In addition, paeonol significantly reversed hemin-induced injury and ferroptosis in neurons, while this phenomenon was notably reversed by HOTAIR overexpression. Moreover, paeonol notably inhibited ferroptosis in hemin-treated neuronal cells via inhibition of ACSL4. Additionally, HOTAIR bound to UPF1, and UPF1 promoted the degradation of ACSL4 by binding to ACSL4. Furthermore, HOTAIR overexpression reversed paeonol-induced inhibition of ferroptosis by mediating the UPF1/ACSL4 axis. Paeonol inhibits the progression of ICH by mediating the HOTAIR/UPF1/ACSL4 axis. Therefore, paeonol might serve as a new agent for the treatment of ICH.

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Section: Introductionmentioning

confidence: 99%

Paeonol inhibits the progression of intracerebral haemorrhage by mediating the HOTAIR/UPF1/ACSL4 axis

et al. 2021

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“…All the post-transcriptional steps in neurodevelopment have one main goal to efficiently control the spatiotemporal amounts of particular proteins. However, high throughput sequencing studies on neurological diseases have revealed that many of mutations exist in the post-transcriptional regulators, which in turn, induce neurodevelopmental and neurodegenerative inherited disorders by unbalanced protein expressions (Deka et al, 2021;Scheper et al, 2007). Importantly, mammals are shown to be highly sensitive to mRNA translation errors.…”

Section: Discussionmentioning

confidence: 99%

“…Exon junction complex (EJC) is an RNA binding complex composed of three core proteins, EIF4A3 (DDX48), RBM8A (Y14), and MAGOH. The EJC serves as a platform for the binding of peripheral factors which together regulate 1 was based on following references (Banerjee et al, 2013;Bayat et al, 2012;Cleary & Ranum, 2013;Deka et al, 2021;Favaro et al, 2014;Kapur & Ackerman, 2018;Karaca et al, 2015;Lagier-Tourenne et al, 2010;Lessel et al, 2017;Najmabadi et al, 2011;Pilaz et al, 2016;Reuter et al, 2017;Ruzzo et al, 2019;Saffary & Xie, 2011;Scheper et al, 2007;Voineagu et al, 2011;Webb et al, 2015).…”

Section: Mrna Translation Gone Wrong In Diseasesmentioning

confidence: 99%

“…In humans, up-frameshift suppressor 3 (UPF3) functions on diverse cellular processes, including NMD, translation, and genetic compensation response. Genome-wide and transcriptome-wide sequencing analyses of patient samples revealed that loss of UPF3B is associated with brain disorders such as intellectual disability, autism, attention deficit hyperactivity disorder, and schizophrenia (Deka et al, 2021). Poly(A)-binding nuclear protein 1 (PABPN1) plays key roles in post-transcriptional processing of RNA.…”

Section: Mrna Translation Gone Wrong In Diseasesmentioning

confidence: 99%

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Making sense of mRNA landscapes: Translation control in neurodevelopment

et al. 2021

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Like all other parts of the central nervous system, the mammalian neocortex undergoes temporally ordered set of developmental events, including proliferation, differentiation, migration, cellular identity, synaptogenesis, connectivity formation, and plasticity changes. These neurodevelopmental mechanisms have been characterized by studies focused on transcriptional control. Recent findings, however, have shown that the spatiotemporal regulation of posttranscriptional steps like alternative splicing, mRNA traffic/localization, mRNA stability/decay, and finally repression/derepression of protein synthesis (mRNA translation) have become just as central to the neurodevelopment as transcriptional control. A number of dynamic players act post-transcriptionally in the neocortex to regulate these steps, as RNA binding proteins (RBPs), ribosomal proteins (RPs), long non-coding RNAs, and/or microRNA. Remarkably, mutations in these post-transcriptional regulators have been associated with neurodevelopmental, neurodegenerative, inherited, or often co-morbid disorders, such as microcephaly, autism, epilepsy, intellectual disability, white matter diseases, Rett-syndrome like phenotype, spinocerebellar ataxia, and amyotrophic lateral sclerosis. Here, we focus on the current state, advanced methodologies and pitfalls of this exciting and upcoming field of RNA metabolism with vast potential in understanding fundamental neurodevelopmental processes and pathologies.

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“…Several studies showed that UPF3B acts as a multifunctional protein, as described in a recent review [4]. UPF3B is involved in various protein-protein interactions (PPIs), which results in known biological functions.…”

Section: Introductionmentioning

confidence: 94%

CRISPR/Cas9-Mediated Gene-Knockout of <em>UPF3B</em> Alters Expression of Cell Cycle and Neuron-Specific Genes

Chandra¹,

Deka²,

Kumari³

et al. 2021

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UPF3B is a constituent of the classical nonsense-mediated mRNA decay (NMD) pathway that degrades both the aberrant transcripts and a set of physiological transcripts. In higher eukaryotes, UPF3B have significant biochemical functions in diverse cellular processes including NMD and translation. UPF3B plays a crucial role in neuronal development and differentiation. Next-generation sequencing technologies identified several loss-of-function mutations in the UPF3B gene that results in neuro-developmental disorders in humans. To uncover the mechanistic role of UPF3B in neuronal functions, we have generated the UPF3B-knockout mammalian cell line model system using CRISPR-Cas9 gene editing method. RNA-Sequencing Analysis of cellular transcriptome from UPF3B-KO cells identified specific genes involved in cell growth and neuronal functions. Altered expression of genes related to the axon guidance pathway delineated the UPF3B function to regulate the neuron-specific genes. Functional enrichment analysis identified the genes involved in the disorders related to mental health and intellectual disability. Our study has the potential to identify the direct players of intellectual disability and will have broader implications.

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Functional roles of human Up-frameshift suppressor 3 (UPF3) proteins: From nonsense-mediated mRNA decay to neurodevelopmental disorders

Cited by 12 publications

References 108 publications

Paeonol inhibits the progression of intracerebral haemorrhage by mediating the HOTAIR/UPF1/ACSL4 axis

Paeonol inhibits the progression of intracerebral haemorrhage by mediating the HOTAIR/UPF1/ACSL4 axis

Making sense of mRNA landscapes: Translation control in neurodevelopment

CRISPR/Cas9-Mediated Gene-Knockout of <em>UPF3B</em> Alters Expression of Cell Cycle and Neuron-Specific Genes

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