Eukaryotic gene expression: understanding the role of UPF1 in global mRNA processing and amyotrophic lateral sclerosis (ALS)

UPF 1是一种RNA解旋酶，通常讨论其在调节无义介导的mRNA衰变（NMD）中的细胞质作用。NMD是一种质量控制机制，能够检测和降解异常mRNA。NMD对于药物靶向特别感兴趣，因为它涉及mRNA调控的许多步骤。引人注目的是，UPF 1是肌萎缩性侧索硬化症（ALS）的候选药物，因为有证据表明人UPF 1的表达恢复ALS大鼠模型中的运动功能（杰克逊等人，2015）。然而，UPF 1的功能作用仍然没有定论。最近的证据表明，UPF 1在果蝇的细胞核中起作用，在那里它与允许适当mRNA包装和输出的活性基因相关联（Singh等人，2019年）。尽管如此，UPF 1对新生mRNA的招募及其核作用仍然知之甚少。这些作用对于正确理解UPF 1如何用作神经退行性疾病的药物靶标至关重要。该项目结合了湿实验室和干实验室程序，以解决UPF 1在全球mRNA加工中的作用。有证据表明，在UPF 1耗尽的条件下，形成核聚集体，这意味着该蛋白质是转录组稳态所需的（Singh等人，2019年）。因此，包括RNA-seq，ChIP-seq和SLAM-seq在内的技术将显示UPF 1如何相互作用并影响pre-mRNAs，探索其与新生转录本的关联及其在适当剪接，包装和输出中的作用。

UPF1 is an RNA helicase commonly discussed for its cytoplasmic roles in modulating nonsense-mediated mRNA decay (NMD). NMD is a quality control mechanism which enables the detection and degradation of aberrant mRNAs. NMD is of particular interest for drug targeting, as it involves many steps of mRNA regulation. Strikingly, UPF1 is a candidate drug for amyotrophic lateral sclerosis (ALS) as there is evidence that expression of human UPF1 restores motor function in a rat model of ALS (Jackson et al., 2015). However, the functional roles of UPF1 remain inconclusive. Recent evidence shows that UPF1 functions in the nuclei of Drosophila, where it associates with active genes allowing for appropriate mRNA packaging and export (Singh et al., 2019). Despite this, UPF1 recruitment to nascent mRNAs and its nuclear roles remain poorly understood. Such roles are crucial to uncover for the appropriate understanding of how UPF1 can be used as a drug target in neurodegenerative diseases. This project combines wet and dry-lab procedures to address the roles of UPF1 on global mRNA processing. Evidence shows that in UPF1 depleted conditions, nuclear aggregates form, meaning this protein is required for transcriptome homeostasis (Singh et al., 2019). Thus, techniques including RNA-seq, ChIP-seq and SLAM-seq will show how UPF1 interacts and affects pre-mRNAs exploring its association with nascent transcripts and its roles in their appropriate splicing, packaging and export.