A07: Speed vs. fidelity: The role of nuclear RNA export under cellular stress

Nuclear mRNA export constitutes a dynamic and tightly regulated process essential for segregating RNAs that perform their function inside the nucleus from other transcripts destined for cytosolic functions. This sorting necessitates a high degree of selectivity to guarantee accuracy. Moreover, the export of mRNA to the cytosol serves as a checkpoint, eliminating inaccurately transcribed or processed mRNAs, as well as mRNAs inadequately loaded with essential RNA-binding proteins, known as guard proteins, within the nucleus (Wickramasinghe & Laskey, 2015). Under stress conditions, the urgency of response permits the circumvention of this checkpoint through alternate export pathways, facilitating uncontrolled exportation (Zander & Krebber, 2017). Notably, standard mRNA export is impeded during stress, whereas stress-responsive mRNAs promptly exit the nucleus, sidestepping the conventional quality control measures (Zander et al. 2016; Hochberg-Laufer et al. 2019). Thus, mRNA export serves as a quality control mechanism that may mitigate the consequences of reduced fidelity of mRNA production.

The overall aim of this project is to understand the complex decision-making involved in choosing mRNA export routes and bypassing quality control mechanisms during cellular stress. Our primary focus is to delineate the factors and pathways that control homeostasis during oxidative stress in human cells. To this end, we aim to quantify RNA metabolism on a global level and thereby identify transcripts that are able to escape quality control during oxidative stress. We will use a combination of experimental and computational methods, including advanced RNA labeling and sequencing techniques, high-resolution.