Increase of a group of PTC(+) transcripts by curcumin through inhibition of the NMD pathway.
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.
Department 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.
Dairong
D
Feng
Department of Medical Microbiology, Faculty of Medicine, University of Manitoba, Winnipeg MB R3E 0J9, Canada.
Ruey-Chyi
RC
Su
Department of Pediatrics, Chinese PLA General Hospital, Beijing 100853, China.
Liping
L
Zou
Department of Biochemistry & Medical Genetics, Faculty of Medicine, University of Manitoba, Winnipeg MB R3E 0J9, Canada.
Barbara
B
Triggs-Raine
Department of Medical Genetics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College Beijing 100005, China. Electronic address: hsz_pumc@ibms.pumc.edu.cn.
Shangzhi
S
Huang
Department of Physiology and Pathophysiology, Faculty of Medicine, University of Manitoba, Winnipeg MB R3E 0J9, Canada. Electronic address: xiej@umanitoba.ca.
Jiuyong
J
Xie
D002478:Cells, Cultured; D018389:Codon, Nonsense / Q000235:genetics*; D003474:Curcumin / Q000494:pharmacology*; D005347:Fibroblasts / Q000187:drug effects / Q000502:physiology; D006801:Humans; D053858:Metabolic Networks and Pathways / Q000187:drug effects / Q000235:genetics; D059365:Nonsense Mediated mRNA Decay / Q000187:drug effects*; D009687:Nuclear Proteins / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000235:genetics; D000068103:Serine-Arginine Splicing Factors; D013661:Tay-Sachs Disease / Q000235:genetics / Q000378:metabolism; D061806:Transcription Termination, Genetic / Q000187:drug effects*; D054820:beta-Hexosaminidase alpha Chain / Q000235:genetics / Q000378:metabolism
D018389:Codon, Nonsense; D009687:Nuclear Proteins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D000068103:Serine-Arginine Splicing Factors; C518253:HEXA protein, human; D054820:beta-Hexosaminidase alpha Chain; D003474:Curcumin
Curcumin; HEXA; Nonsense-mediated decay; Premature termination codon; SRSF1; UPF1