Biology subjects

McGirr, T.

Publications and source records attributed to McGirr, T..

3 recordsLinked to original sources

bioRxiv2026

GIGYF2/4EHP-Mediated Translational Attenuation Maintains Cellular Homeostasis Following Ionizing Radiation

Translational regulation is a critical component of the cellular response to environmental stress. Ionizing radiation (IR) exists naturally at low doses (e.g., cosmic rays and radioactive materials) but is applied at much higher doses in clinical settings, where accelerated photons (X-rays) and particle beams (protons, ions etc) are utilized for the treatment of cancer. While the effects of IR on DNA damage and cell cycle are well established, its impacts on cellular RNA metabolism remains less understood. In particular, the role of the mRNA translation machinery in shaping the early cellular response to IR is largely unexplored. Here, we demonstrate that IR induces an acute and persistent translational repression. This acute repression is independent of the mTOR and Integrated Stress Response pathways, which are known regulators of mRNA translation in response to environmental cues. Instead, we discovered that the translational repression is, at least partially, mediated by the GIGYF2/4EHP translational repressor complex. We show that GIGYF2/4EHP recruitment to the mRNAs upon IR exposure is driven by rapidly enhanced interactions with RNA-binding proteins such as ZFP36 and components of the miRNA-Induced Silencing Complex (miRISC) that are poised on their target mRNAs. Importantly, the presence of the GIGYF2/4EHP complex is required for the maintenance of proteostasis and cell viability following irradiation. Together, our results establish mRNA translational control as a key determinant of cellular response to IR and identify GIGYF2/4EHP as a critical component of this adaptive mechanism.

cell biology↗

bioRxiv2025

Codon-dependent regulation of mRNA translation and stability by ZC3H7A and ZC3H7B RNA-binding proteins

Decelerated translation elongation caused by non-optimal codons can reduce mRNA stability through codon optimality-mediated mRNA degradation. A key element of this process is the coupling of sensing the mRNA codon usage with the regulation of translation efficiency and stability. We report that two paralog RNA-binding proteins (ZC3H7A and ZC3H7B), which are only found in Chordates, preferentially bind to and reduce the stability and translation of mRNAs enriched in non-optimal codons with A/U at their wobble sites (A/U3 codons). ZC3H7A/B engage with ribosomes that lack elongation factors and induce mRNA degradation or block translation initiation through their interactions with the CCR4-NOT and the GIGYF2/4EHP translation repressor complex, respectively. Depletion of ZC3H7A/B or 4EHP impairs the repression of non-optimal A/U3-rich mRNAs. This study provides insights into a unique mechanism in higher eukaryotes that couples codon usage with the regulation of translation efficiency and mRNA stability.

cell biology↗

bioRxiv2023

Ribosome Quality Control Mechanism Mitigates the Cytotoxic Impacts of Ribosome Collisions Induced by 5-Fluorouracil

Translation of aberrant or damaged mRNAs results in ribosome stalling and collisions. The Ribosome Quality Control (RQC) mechanism detects collided ribosomes and removes aberrant mRNAs and nascent peptides, thus preventing their cytotoxic effects. Conversely, excessive or unresolved ribosome collisions can induce apoptosis. 5-Fluorouracil (5FU) forms the backbone of standard-of-care chemotherapeutic regimens for several types of cancer. Although best known for its incorporation into DNA and inhibition of thymidylate synthase, a major determinant of 5FUs anticancer activity is its incorporation into RNAs. Nevertheless, the mechanism(s) underlying RNA-dependent 5FU cytotoxicity and the cellular response to its impact on RNA metabolism remain unclear. Here, we report a key role for RQC in mitigating the cytotoxic effects of 5FU-induced dysregulation of mRNA translation. We show that acute 5FU treatment results in the rapid induction of the mTOR signalling pathway, an enhanced rate of mRNA translation initiation, and increased ribosome collisions that trigger RQC. We also found that RQC deficiency, caused by the depletion of ZNF598, results in increased 5FU-induced cell death, a phenotype that is reversed by inhibition of mTOR or repression of mRNA translation initiation. Importantly, 5FU treatment enhances the expression of key RQC factors, including ZNF598 and GIGYF2, via an mTOR-dependent post-translational regulation mechanism. This acute adaptation likely mitigates the cytotoxic consequences of increased ribosome collisions upon 5FU treatment. Overall, our data indicate a heretofore unknown mTOR-dependent mechanism that augments the RQC process, mitigating the cytotoxicity of 5FU and undermining its anticancer efficacy.

cell biology↗