无义介导的 mRNA 衰变:机制见解和生理意义,Molecular Biotechnology

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无义介导的 mRNA 衰变:机制见解和生理意义,Molecular Biotechnology

2024-07-12 02:47| 来源: 网络整理| 查看: 265

无义介导的 mRNA 衰减 (NMD) 是真核生物中进化上保守的监视机制,也调节生理转录本的表达,从而参与基因调控。它本质上确保了异常转录本的识别和删除。因此,NMD 通过限制截短蛋白质的合成(可能是通过消除有缺陷的 mRNA)来保护细胞系统。NMD 是真核生物中进化上保守的监视机制,也调节生理转录本的表达,因此也参与基因调控。NMD 机器主要扫描并区分异常和非异常转录本。由于截短蛋白的产生,会出现多种细胞功能障碍,因此 NMD 核心蛋白、移码因子 (UPF) 会识别有缺陷的 mRNA,并进一步招募导致 mRNA 降解的因子。NMD 在调节细胞机制(包括病理和生理事件)方面表现出惊人的可变性。但是,NMD 的详细潜在分子机制仍然模糊,需要进行广泛的研究才能深入了解细胞稳态。由于涉及大量蛋白质、分子相互作用及其在该过程的不同步骤中的功能,因此理解 NMD 途径变得复杂。此外,选择性剪接等方法会产生大量 mRNA 亚型,因此很难理解选择性剪接对 NMD 功能效率的影响。NMD 在癌症发展中的作用非常复杂。研究表明,在某些情况下,癌细胞利用NMD通路作为工具,利用NMD机制来维持肿瘤微环境。更深入地了解肿瘤如何利用 NMD 通路发挥作用的复杂机制,可以制定针对和抑制参与促肿瘤活性的 NMD 因子的策略。关于 NMD 通路以及它如何区分 NMD 靶向的 mRNA 和非 NMD 的 mRNA 的信息非常少。这篇综述强调了我们目前对 NMD 的理解,特别是监管机制,并试图概述需要进一步调查的较少探索的问题。总体而言,对 NMD 机制的详细分子理解可能会带来广泛的应用,以改善细胞稳态,并制定对抗病理性疾病的战略,从而朝着实现联合国可持续发展目标(SDG 3:良好的健康和福祉)迈进。存在)。

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Nonsense-Mediated mRNA Decay: Mechanistic Insights and Physiological Significance

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).

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