Disease relevance of UPF1

• In this study, we evaluated the effects of NMD inhibition by siRNA-mediated knockdown of SMG-1 or Upf1 on the phenotype of Ullrich disease, an autosomal recessive congenital muscular dystrophy [1].
• Acute renal failure, oliguric (ORF) in ten and nonoliguric (NORF) in another ten patients, was observed [2].

Psychiatry related information on UPF1

• In the frontal cortex (FC) of the normally aging human brain, glutathione (GSH) and its novel analogue, UPF1, stimulate G proteins more than in Alzheimer's disease (AD) FC [3].

High impact information on UPF1

• Stau1 binds directly to Upf1 and elicits mRNA decay when tethered downstream of a termination codon [4].
• Importantly, an association between SURF and the EJC is required for SMG-1-mediated Upf1 phosphorylation and NMD [5].
• Further, we describe a novel complex that contains the NMD factors SMG-1 and Upf1, and the translation termination release factors eRF1 and eRF3 (SURF) [5].
• Thus, the SMG-1-mediated phosphorylation of Upf1 occurs on the association of SURF with EJC, which provides the link between the EJC and recognition of PTCs and triggers NMD [5].
• Specific decapping factors interact with the mRNA decay activators hUpf1 and TTP, and TTP enhances decapping of a target AU-rich element (ARE) RNA in vitro [6].

Biological context of UPF1

• In metazoa, regulation of the phosphorylation state of UPF1 is crucial for nonsense-mediated mRNA decay (NMD), a process by which aberrant mRNAs containing nonsense mutations are degraded [7].
• The human RNA surveillance factor UPF1 is required for S phase progression and genome stability [8].
• We have now cloned a human cDNA whose deduced amino acid sequence shows the highest degree of homology to that of UPF1, a bona fide Saccharomyces cerevisiae group I RNA helicase required for accelerated degradation of nonsense mRNA [9].
• However, we have recently demonstrated that human UPF1 is also essential for DNA replication and S phase progression [10].
• Additionally, rent1/hUpf1 enters the nucleus where it may directly influence early events in mRNA biogenesis [11].

Anatomical context of UPF1

• Hupf1-2tag is localized in the cytoplasm similar to the endogenous Hupf1 protein, and the Hupf1-2tag cell line is fully NMD-competent [12].
• Inhibition of rent1/hUpf1 expression abrogated both NMD and NAS of nonsense T cell receptor beta transcripts [11].
• Specific inhibition of nonsense-mediated mRNA decay components, SMG-1 or Upf1, rescues the phenotype of ullrich disease fibroblasts [1].
• Here, we demonstrate that the estimated 3 x 10(6) copies of hUpf1 p per exponentially growing HeLa cell are essentially equally distributed among polysomal, subpolysomal, and ribosome-free fractions [13].

Associations of UPF1 with chemical compounds

• Comparison of the yeast and human UPF1 proteins demonstrated that the amino terminal cysteine/histidine-rich region and the region comprising the domains that define this protein as a superfamily group I helicase have been conserved [14].
• When the oxidation is caused by hydroxyl radical (OH*), the gamma-glutamate containing peptides (UPF1 and UPF6) exhibited two to four times higher antioxidative activity (k(II) = 4.428 and 2.152 x 10(3)/M.min, respectively) [15].
• Two novel glutathione analogues, UPF1 and UPF15, have been designed and synthesised [16].
• Upf1/Upf2 Regulation of 3' Untranslated Region Splice Variants of AUF1 Links Nonsense-Mediated and A+U-Rich Element-Mediated mRNA Decay [17].

Physical interactions of UPF1

• Phosphorylation of hUPF1 induces formation of mRNA surveillance complexes containing hSMG-5 and hSMG-7 [18].
• SMG5 and SMG7 form a complex with UPF1 and interact with each other via their N-terminal domains [19].
• We also show that P-hUPF1 forms distinct complexes containing different isoforms of hUPF3A [18].
• SMD depends on the recruitment of Upf1 by the RNA-binding protein Stau1 but does not depend on the other Upf proteins [20].

Enzymatic interactions of UPF1

• Our data indicate that hSMG-1 may function in NMD by directly phosphorylating hUpf1 protein at physiologically relevant sites [21].

Regulatory relationships of UPF1

• CBP80 promotes interaction of Upf1 with Upf2 during nonsense-mediated mRNA decay in mammalian cells [20].
• In the UPF trimeric complex, UPF2 and UPF3b cooperatively stimulate both ATPase and RNA helicase activities of UPF1 [22].

Other interactions of UPF1

• We propose that sequential phosphorylation and dephosphorylation of hUPF1 by hSMG-1 and PP2A, respectively, contribute to the remodeling of the mRNA surveillance complex [18].
• Physical interaction of UPF1 with DNA polymerase delta suggests a role for human UPF1 in DNA synthesis during replication or repair [8].
• MS and immunoblotting identified the NMD factors Hupf2 and Hupf3a/b as interaction partners of Hupf1 [12].
• Moreover, IR exposure triggers hUpf1 phosphorylation at Ser/Thr-Gln motifs, and both ATM and hSMG-1 contribute to these phosphorylation events [23].
• When PTCs were removed from pseudoexon 3B or when UPF1 small interfering RNA was used to impair the NMD mechanism, the decay of the splice variant was reduced, confirming the involvement of NMD in the degradation of CYP3A5 splice variants [24].

Analytical, diagnostic and therapeutic context of UPF1

• Finally, immunofluorescence and Western blot analyses revealed that the human and mouse polypeptides, like yeast UPF1, are expressed in the cytoplasm, but not in the nucleus [9].
• Size-exclusion chromatography indicates that the NMD factors Hupf1, Hupf2 and the large isoform of Hupf3a might exist in a stable, high-molecular-mass complex of approx. 1.3 MDa [12].
• In this study, the stability of UPF1, UPF15 and glutathione in various solutions was investigated by using HPLC and CE [16].
• Ribonucleoprotein immunoprecipitation experiments revealed that both Upf1 and Upf2 can associate with an NMD-sensitive AUF1 mRNA 3'-UTR variant in cells [17].
• We show that the inactivation of NMD by RNAi-mediated knockdown of the essential NMD factor hUpf1 or hSmg6 increases the NMD reporter mRNA level, resulting in a proportional increase of the green fluorescence that can be detected by flow cytometry, spectrofluorometry and fluorescence microscopy [25].

References