Abstract
Human TP53 gene encodes the tumor suppressor p53 and, via alternative splicing, the p53β and γ isoforms. Numerous studies have shown that p53β/γ can modulate p53 functions and are critically involved in regulation of cellular response to stress conditions. However, it is not fully understood how the β and γ isoforms are regulated following splicing. Using gene targeting and RNAi, we showed that depletion of the nonsense-mediated mRNA decay (NMD) factor SMG7 or UPF1 significantly induced p53β but had minimal effect on p53γ. Sequence analysis reveals the presence of unique features – key hallmarks of NMD targets in the p53β transcript, which was further confirmed in NMD reporter gene assays. By manipulating splicing components, we found that NMD activities are crucial to control p53β levels under conditions that favor its splicing. Our data demonstrate that the NMD and alternative splicing pathways regulate p53β in a synergistic manner, and NMD plays a critical role in the determination of the p53β following its splicing. As aberrant p53β expression and dysfunctional NMD are both implicated in cancers, our studies may provide a novel insight into the regulation of p53β in tumorigenic settings.
Highlights
Transcription factor p53 is known for its role in regulating a complex gene network involving the induction of tumor suppressive pathways including senescence, cell cycle arrest and apoptosis[1,2], which can be modulated by its isoforms[3,4,5]
We investigate whether SMG7 can regulate p53 through the nonsense-mediated mRNA decay (NMD) pathway, as p53 isoforms β and γ are derived from alternative splicing of intron 9 and each contain a premature stop codon (PTC) before the last intron[3], a common feature of NMD targets (Fig. 1a)
Here we show that the nonsense-mediated mRNA decay pathway plays a crucial role in the regulation of p53β, as demonstrated by disruption of two core NMD factors SMG7 and UPF1
Summary
Transcription factor p53 is known for its role in regulating a complex gene network involving the induction of tumor suppressive pathways including senescence, cell cycle arrest and apoptosis[1,2], which can be modulated by its isoforms[3,4,5]. The p53 isoforms β and γ which form as a result of alternative splicing, are expressed at relatively low levels and reside predominantly in the nucleus, allowing them to bind differentially to p53 target promoters as potent activators of p53α activity[3,4,5,6,7] Both isoforms have been found to be dysregulated in cancers[8,9,10,11,12,13,14], and implicated in contributing to the p53α tumor suppressive function[11,15]. SRSF7 can be regulated following gamma irradiation, resulting in the induction of alternative splicing of p53β in response to cellular stressors like DNA damage[19]. Our studies reveal an additional mechanism by which SMG7 can regulate p53 as well as demonstrate a novel function of the NMD pathway in regulation of p53β cellular fate
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