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Increase of a group of PTC(+) transcripts by curcumin through inhibition of the NMD pathway
Dairong Feng1, Ruey-Chyi Su2, Liping Zou3
1Department of Medical Genetics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College Beijing 100005, China; Department of Physiology and Pathophysiology, Faculty of Medicine, University of Manitoba, Winnipeg MB R3E 0J9, Canada.
Abstract:
Nonsense-mediated mRNA decay (NMD), an mRNA surveillance mechanism, eliminates premature termination codon-containing (PTC⁺) transcripts. For instance, it maintains the homeostasis of splicing factors and degrades aberrant transcripts of human genetic disease genes. Here we examine the inhibitory effect on the NMD pathway and consequent increase of PTC+ transcripts by the dietary compound curcumin. We have found that several PTC⁺ transcripts including that of serine/arginine-rich splicing factor 1 (SRSF1) were specifically increased in cells by curcumin. We also observed a similar curcumin effect on the PTC⁺ mutant transcript from a Tay-Sachs-causing HEXA allele or from a beta-globin reporter gene. The curcumin effect was accompanied by significantly reduced expression of the NMD factors UPF1, 2, 3A and 3B. Consistently, in chromatin immunoprecipitation assays, curcumin specifically reduced the occupancy of acetyl-histone H3 and RNA polymerase II at the promoter region (-376 to -247nt) of human UPF1, in a time- and dosage-dependent way. Importantly, knocking down UPF1 abolished or substantially reduced the difference of PTC(+) transcript levels between control and curcumin-treated cells. The disrupted curcumin effect was efficiently rescued by expression of exogenous Myc-UPF1 in the knockdown cells. Together, our data demonstrate that a group of PTC⁺ transcripts are stabilized by a dietary compound curcumin through the inhibition of UPF factor expression and the NMD pathway.
Insights
Curcumin, a dietary compound, inhibits nonsense-mediated mRNA decay (NMD) by reducing UPF factor expression. This leads to increased levels of premature termination codon-containing (PTC+) transcripts, offering potential therapeutic insights.
Area of Science:
- Molecular Biology
- Cell Biology
- Pharmacology
Background:
- Nonsense-mediated mRNA decay (NMD) is a crucial surveillance pathway that degrades transcripts containing premature termination codons (PTCs).
- NMD maintains cellular homeostasis and prevents the expression of potentially harmful truncated proteins, including those associated with genetic diseases.
- Aberrant transcripts and those from disease genes are targets for NMD-mediated degradation.
Purpose of the Study:
- To investigate the effect of the dietary compound curcumin on the NMD pathway.
- To determine if curcumin can modulate the levels of premature termination codon-containing (PTC+) transcripts.
- To elucidate the molecular mechanisms underlying curcumin's action on NMD.
Main Methods:
- Cellular assays to measure PTC+ transcript levels following curcumin treatment.
- Analysis of NMD factor (UPF1, UPF2, UPF3A, UPF3B) expression.
- Chromatin immunoprecipitation (ChIP) assays to assess histone modifications and RNA polymerase II occupancy at the UPF1 promoter.
- Gene knockdown and rescue experiments using UPF1.
Main Results:
- Curcumin treatment specifically increased the levels of several PTC+ transcripts, including SRSF1, a HEXA allele mutant, and a beta-globin reporter.
- Curcumin significantly reduced the expression of key NMD factors (UPF1, UPF2, UPF3A, UPF3B).
- Curcumin decreased acetyl-histone H3 and RNA polymerase II occupancy at the UPF1 promoter, indicating transcriptional repression.
- UPF1 knockdown abolished the curcumin-induced increase in PTC+ transcripts, and exogenous UPF1 expression rescued this effect.
Conclusions:
- Curcumin inhibits the NMD pathway by downregulating the expression of UPF factors.
- This inhibition leads to the stabilization and accumulation of PTC+ transcripts.
- Curcumin's modulation of NMD and PTC+ transcripts presents a novel mechanism of action for this dietary compound.
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