Hyperacute response proteins synthesized on γ-tubulin-FTO-MARK4 translation microdomains regulate cancer's acute stress response

  • Cell Rep. 2025 Jul 22;44(7):115871. doi: 10.1016/j.celrep.2025.115871.
Bruno Saleme  1 ,  Saymon Tejay  2 ,  Kléouforo-Paul Dembélé  2 ,  Rabih Abou Farraj  3 ,  Yongneng Zhang  2 ,  Yongsheng Liu  2 ,  Aristeidis E Boukouris  2 ,  Sotirios D Zervopoulos  2 ,  Alois Haromy  2 ,  Yuan-Yuan Zhao  2 ,  Shelly Braun  3 ,  William Saleme  2 ,  Xuejun Sun  4 ,  Richard P Fahlman  3 ,  Mark Glover  3 ,  Adam Kinnaird  5 ,  Gopinath Sutendra  2 ,  Evangelos D Michelakis  6
Affiliations
  • 1. Department of Medicine, University of Alberta, Edmonton, AB T6G 2G5, Canada. Electronic address: [email protected].
  • 2. Department of Medicine, University of Alberta, Edmonton, AB T6G 2G5, Canada.
  • 3. Department of Biochemistry, University of Alberta, Edmonton, AB T6G 2G5, Canada.
  • 4. Department of Oncology, University of Alberta, Edmonton, AB T6G 2G5, Canada.
  • 5. Department of Oncology, University of Alberta, Edmonton, AB T6G 2G5, Canada; Department of Surgery, University of Alberta, Edmonton, AB T6G 2G5, Canada.
  • 6. Department of Medicine, University of Alberta, Edmonton, AB T6G 2G5, Canada. Electronic address: [email protected].
PMID: 40540400 DOI: 10.1016/j.celrep.2025.115871
Abstract

Compared to normal cells, Cancer cells are particularly resistant to stress, and their immediate response to stress is critical for subsequent adaptation, a major clinical challenge. With unbiased proteomics and transcriptomics, we identify a list of hyperacute response proteins (HARPs) translated from pre-existing mRNAs within 20 min of diverse stresses in several Cancer cells, despite the known suppressed global translation in stress. HARP mRNAs are translated on microtubule-associated translation microdomains (MATMs) located on γ-tubulin, which host FTO and specialized distinct cytoskeletal ribosomes. FTO exits the nucleus immediately after stress and is activated by microtubule-associated kinase MARK4, demethylating a translation-inhibiting m6A mRNA methylation signature and facilitating compartmentalized HARP translation on MATMs, while non-HARP mRNAs remain inhibited. FTO or MARK4 inhibition suppresses HARP synthesis and increases Apoptosis after various stresses, including chemotherapy. γ-tubulin, FTO, and MARK4 are therapeutic targets, as they comprehensively promote HARP translation, a potential Achilles' heel for cancer's resistance to physiologic or therapeutic stress.

Keywords
CP: Cancer; CP: Molecular biology; cancer resistance; m6A; microtubules; ribosomes; stress response; translation; γ-tubulin.
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