2. Academic Validation
  3. Hyperacute response proteins synthesized on γ-tubulin-FTO-MARK4 translation microdomains regulate cancer's acute stress response

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

Affiliations

  • 1 Department of Medicine, University of Alberta, Edmonton, AB T6G 2G5, Canada. Electronic address: bsaleme@ualberta.ca.
  • 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: em2@ualberta.ca.
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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