The RNA helicase DHX34 functions as a scaffold for SMG1-mediated UPF1 phosphorylation

Melero, Roberto; Hug, Nele; López-Perrote, Andrés; Yamashita, Akio; Cáceres, Javier F.; Llorca, Óscar

doi:10.1038/ncomms10585

Cited by 42 publications

(47 citation statements)

References 51 publications

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“…In mammalian cells, the discrimination of PTC-containing transcripts depends on the position of PTC in mRNA. Transcripts containing PTC at least 50-55 nucleotides upstream of the last exon-exon cell lysates, and preferentially binds with the hypophosphorylated UPF1 [27][28][29]. It is proposed that DHX34 is involved in the activation of UPF1 phosphorylation, and mediates a change in interaction patterns within the NMD, which propagates NMD activation [28][29][30].…”

Section: The Nonsense-mediated Mrna Decay (Nmd) Pathway and Machinerymentioning

confidence: 99%

“…Transcripts containing PTC at least 50-55 nucleotides upstream of the last exon-exon cell lysates, and preferentially binds with the hypophosphorylated UPF1 [27][28][29]. It is proposed that DHX34 is involved in the activation of UPF1 phosphorylation, and mediates a change in interaction patterns within the NMD, which propagates NMD activation [28][29][30]. PC: C-terminal proline-rich region; HEAT: Huntingtin, elongation factor 3 (EF3), protein phosphatase 2A (PP2A), yeast kinase TOR1 domain; FAT: focal adhesion kinase domain; FRB: FKBP12-rapamycin-binding; PIKK: phosphatidylinositol 3-kinase-related protein kinase domain; FATC: C-terminal FAT domain; G-fold-like: domains involved in dimerization between SMG8-SMG9 [31-33].…”

Section: The Nonsense-mediated Mrna Decay (Nmd) Pathway and Machinerymentioning

confidence: 99%

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Nonsense-Mediated mRNA Decay: Pathologies and the Potential for Novel Therapeutics

Pawlicka

Kalathiya

Alfaro

2020

Cancers

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Nonsense-mediated messenger RNA (mRNA) decay (NMD) is a surveillance pathway used by cells to control the quality mRNAs and to fine-tune transcript abundance. NMD plays an important role in cell cycle regulation, cell viability, DNA damage response, while also serving as a barrier to virus infection. Disturbance of this control mechanism caused by genetic mutations or dys-regulation of the NMD pathway can lead to pathologies, including neurological disorders, immune diseases and cancers. The role of NMD in cancer development is complex, acting as both a promoter and a barrier to tumour progression. Cancer cells can exploit NMD for the downregulation of key tumour suppressor genes, or tumours adjust NMD activity to adapt to an aggressive immune microenvironment. The latter case might provide an avenue for therapeutic intervention as NMD inhibition has been shown to lead to the production of neoantigens that stimulate an immune system attack on tumours. For this reason, understanding the biology and co-option pathways of NMD is important for the development of novel therapeutic agents. Inhibitors, whose design can make use of the many structures available for NMD study, will play a crucial role in characterizing and providing diverse therapeutic options for this pathway in cancer and other diseases.

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Section: The Nonsense-mediated Mrna Decay (Nmd) Pathway and Machinerymentioning

confidence: 99%

Section: The Nonsense-mediated Mrna Decay (Nmd) Pathway and Machinerymentioning

confidence: 99%

Nonsense-Mediated mRNA Decay: Pathologies and the Potential for Novel Therapeutics

Pawlicka

Kalathiya

Alfaro

2020

Cancers

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“…The so‐called SURF complex (consisting of SMG1 and its regulators SMG8 and SMG9, hypophosphorylated UPF1, ERF1, and ERF3) was shown to interact with DHX34 . Recent structural and biochemical data indicate that DHX34 might function as a scaffold to recruit UPF1 to SMG1 . DHX34 further promotes the interaction of UPF2 with UPF1 and UPF2 in turn was shown to induce a large conformational change in UPF1, to stimulate UPF1's helicase activity, and to promote SMG1 kinase activity by dissociating SMG8 from SMG1, finally resulting in the phosphorylation of UPF1 .…”

Section: Current Working Model For Nmdmentioning

confidence: 99%

Nonsense‐mediated mRNA decay: novel mechanistic insights and biological impact

2016

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Nonsense-mediated mRNA decay (NMD) was originally coined to define a quality control mechanism that targets mRNAs with truncated open reading frames due to the presence of a premature termination codon. Meanwhile, it became clear that NMD has a much broader impact on gene expression and additional biological functions beyond quality control are continuously being discovered. We review here the current views regarding the molecular mechanisms of NMD, according to which NMD ensues on mRNAs that fail to terminate translation properly, and point out the gaps in our understanding. We further summarize the recent literature on an ever-rising spectrum of biological processes in which NMD appears to be involved, including homeostatic control of gene expression, development and differentiation, as well as viral defense.

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“…Next, UPF1 phosphorylation is stimulated by the recruitment of UPF2 and DHX34 [75][76][77]. UPF2 may be recruited to the vicinity of UPF1 through an interaction with UPF3B [78,79].…”

Section: Upf1 Triggers Mrna Degradationmentioning

confidence: 99%

An Antiviral Process Targeting HTLV-1: The Complex Relationship between HTLV-1 and Nonsense-mediated mRNA Decay

Prochasson¹,

Jalinot²,

Mocquet³

2020

Preprint

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Before the adaptive immune response is established, retroviruses can be targeted by several cellular host factors at different stages of the viral replication cycle. This intrinsic immunity relies on a large diversity of antiviral processes. In the case of HTLV-1 infection, these active innate host defence mechanisms are debated. Among these mechanisms, we focused on a RNA decay pathway called nonsense-mediated mRNA decay (NMD), which can target multiple viral RNAs, including HTLV-1 unspliced RNA, as it has been recently demonstrated. NMD is a cotranslational process that depends on the RNA helicase UPF1 and regulates the expression of multiple types of host mRNAs. RNA sensitivity to NMD depends on mRNA organization and the ribonucleoprotein (mRNP) composition.HTLV-1 has evolved several means to evade the NMD threat, leading to NMD inhibition. In the early steps of infection, NMD inhibition favours the production of HTLV-1 infectious particles, which may contribute to the survival of the most fit clones despite genome instability; however, its direct longterm impact remains to be investigated.

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The RNA helicase DHX34 functions as a scaffold for SMG1-mediated UPF1 phosphorylation

Cited by 42 publications

References 51 publications

Nonsense-Mediated mRNA Decay: Pathologies and the Potential for Novel Therapeutics

Nonsense-Mediated mRNA Decay: Pathologies and the Potential for Novel Therapeutics

Nonsense‐mediated mRNA decay: novel mechanistic insights and biological impact

An Antiviral Process Targeting HTLV-1: The Complex Relationship between HTLV-1 and Nonsense-mediated mRNA Decay

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