TACC3-driven translation reprogramming dictates susceptibility or tolerance to mitotic stress
- 1Medical University of South Carolina
Abstract
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.
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BibTeX
@misc{saatci2026tacc3driven,
title = {{TACC3-driven translation reprogramming dictates susceptibility or tolerance to mitotic stress}},
author = {O. Saatci and A. Hernandez-Corchado and A. Aguilar-Mahecha and B. Howley and J. R. Bethard and J.-S. Anoma and J. Lafleur and M. Buchanan and E. G. Hill and L. E. Ball and M. Sajish and P. Howe and M. Basik and H. Najafabadi and O. Sahin},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.18.752750},
url = {https://www.biorxiv.org/content/10.64898/2026.09.18.752750v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - TACC3-driven translation reprogramming dictates susceptibility or tolerance to mitotic stress
AU - O. Saatci
AU - A. Hernandez-Corchado
AU - A. Aguilar-Mahecha
AU - B. Howley
AU - J. R. Bethard
AU - J.-S. Anoma
AU - J. Lafleur
AU - M. Buchanan
AU - E. G. Hill
AU - L. E. Ball
AU - M. Sajish
AU - P. Howe
AU - M. Basik
AU - H. Najafabadi
AU - O. Sahin
PY - 2026
DA - 2026/09/18
PB - bioRxiv
DO - 10.64898/2026.09.18.752750
UR - https://www.biorxiv.org/content/10.64898/2026.09.18.752750v1
AB - 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.
ER -