Biology subjects

Hill, E. G.

Publications and source records attributed to Hill, E. G..

2 recordsLinked to original sources

bioRxiv2026

TACC3-driven translation reprogramming dictates susceptibility or tolerance to mitotic stress

Translation reprogramming is central to cancer cell plasticity under stress. However, the molecular players coordinating translation and epitranscriptomic rewiring to determine adaptive responses to mitotic stress remain elusive. Here, we found that microtubule targeting agent (MTA)-induced CDK1 blocks global translation while it phosphorylates and degrades TACC3, a multifunctional adaptor, releasing eIF4A/eIF4E/eIF4G2 initiation factors. This promotes selective m7G cap-dependent translation of mRNAs with MTAup motif that are functionally required for apoptosis by disrupting proteostasis, promoting MTA-sensitivity. On the other hand, selectively translated TACC3 interacts with eIF3d/eIF4G1 and the m6A writer METTL3, mediating switch to m6A methylation and m7G cap-independent translation of mRNAs with hnRNPC-motif involved in chromosome segregation, driving MTA tolerance. TACC3 inhibition overcomes MTA resistance via restoring translation reprogramming. These findings demonstrate that TACC3 is a pivotal coordinator of translation/epitranscriptomic reprogramming and a therapeutic target in MTA-refractory cancers.

cancer biology↗

bioRxiv2022

Stress-Mediated Attenuation of Translation Undermines T Cell Tumor Control

Protein synthesis enables cell growth and survival, but the molecular mechanisms through which T cells suppress or maintain protein translation in the stress of solid tumors are unknown. Using mouse models and human tumors we demonstrate that protein translation in T cells is repressed by the solid tumor microenvironment (TME) due to activation of the unfolded protein response (UPR) via phosphorylation of the subunit of eukaryotic translation initiation factor 2 (p-eIF2). Given that acute glucose deprivation in T cells exacerbated p-eIF2, we show that metabolic reprogramming toward glycolytic independence allays the UPR and p-eIF2, enabling sustained protein translation in T cells in TME stress. UPR mitigation was associated with enhanced degradation of proteins in antitumor T cells, as proteasome inhibition resulted in eIF2 phosphorylation, attenuation of translation, and loss of antitumor efficacy. In contrast, proteasome stimulation relieved translation inhibition, inducing robust T cell tumor control, offering a new therapeutic avenue to fuel the efficacy of tumor immunotherapy.

immunology↗