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

Bruno Saleme; Saymon Tejay; Kléouforo-Paul Dembélé; Rabih Abou Farraj; Yongneng Zhang; Yongsheng Liu; Aristeidis E Boukouris; Sotirios D Zervopoulos; Alois Haromy; Yuan-Yuan Zhao; Shelly Braun; William Saleme; Xuejun Sun; Richard P Fahlman; Mark Glover; Adam Kinnaird; Gopinath Sutendra; Evangelos D Michelakis

doi:10.1016/j.celrep.2025.115871

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

Cell Rep. 2025 Jun 18;44(7):115871. doi: 10.1016/j.celrep.2025.115871. Online ahead of print.

Authors

Bruno Saleme¹, Saymon Tejay², Kléouforo-Paul Dembélé², Rabih Abou Farraj³, Yongneng Zhang², Yongsheng Liu², Aristeidis E Boukouris², Sotirios D Zervopoulos², Alois Haromy², Yuan-Yuan Zhao², Shelly Braun³, William Saleme², Xuejun Sun⁴, Richard P Fahlman³, Mark Glover³, Adam Kinnaird⁵, Gopinath Sutendra², Evangelos D Michelakis⁶

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.