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

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.