Nonsense-Mediated mRNA Decay: Mechanistic Insights and Physiological Significance.

Abstract

Nonsense-mediated mRNA decay (NMD) is an evolutionarily conserved surveillance mechanism across eukaryotes and also regulates the expression of physiological transcripts, thus involved in gene regulation. It essentially ensures recognition and removal of aberrant transcripts. Therefore, the NMD protects the cellular system by restricting the synthesis of truncated proteins, potentially by eliminating the faulty mRNAs. NMD is an evolutionarily conserved surveillance mechanism across eukaryotes and also regulates the expression of physiological transcripts, thus involved in gene regulation as well. Primarily, the NMD machinery scans and differentiates the aberrant and non-aberrant transcripts. A myriad of cellular dysfunctions arise due to production of truncated proteins, so the NMD core proteins, the up-frameshift factors (UPFs) recognizes the faulty mRNAs and further recruits factors resulting in the mRNA degradation. NMD exhibits astounding variability in its ability in regulating cellular mechanisms including both pathological and physiological events. But, the detailed underlying molecular mechanisms in NMD remains blurred and require extensive investigation to gain insights on cellular homeostasis. The complexity in understanding of NMD pathway arises due to the involvement of numerous proteins, molecular interactions and their functioning in different steps of this process. Moreover methods such as alternative splicing generates numerous isoforms of mRNA, so it makes difficulties in understanding the impact of alternative splicing on the efficiency of NMD functioning. Role of NMD in cancer development is very complex. Studies have shown that in some cases cancer cells use NMD pathway as a tool to exploit the NMD mechanism to maintain tumor microenvironment. A greater level of understanding about the intricate mechanism of how tumor used NMD pathway for their benefits, a strategy can be developed for targeting and inhibiting NMD factors involved in pro-tumor activity. There are very little amount of information available about the NMD pathway, how it discriminate mRNAs that are targeted by NMD from those that are not. This review highlights our current understanding of NMD, specifically the regulatory mechanisms and attempts to outline less explored questions that warrant further investigations. Taken as a whole, a detailed molecular understanding of the NMD mechanism could lead to wide-ranging applications for improving cellular homeostasis and paving out strategies in combating pathological disorders leaping forward toward achieving United Nations sustainable development goals (SDG 3: Good health and well-being).