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We previously showed that the adaptive response of BRAFV600-mutated melanoma cells to BRAF inhibition emerges from a subpopulation of cells expressing an intermittent lower level of the mRNA-binding protein HuR. In this study, following initial overexpression experiments in which we confirm our previous results, we use wild-type and mutants HuR full-length mRNA constructs and in vivo-interacting assays and demonstrate that a highly conserved interferon-γ-activated inhibitor of translation (GAIT)-like motif located upstream of the GU-rich elements of HuR major polyadenylation site (PAS2), interacts with constituents of the GAIT complex and affects HuR post-transcriptional expression regulation. Knockdown of the ribosomal protein L13a or the inhibition of the DAPK1-ZIPK axis involved in L13a phosphorylation, reduces the proportion of HuR L ow cells at steady-state and attenuates the adaptive response of the whole melanoma-cell population to BRAF inhibition. These results have further potential therapeutic implications for disease conditions associated with HuR insufficient expression., Competing Interests: Declaration of competing interest Rastine Merat is inventor on a patent on the use of agents enhancing HuR/ELAV protein levels in the treatment of BRAF-mutated cancers. No conflicts of interest for F. Noulet., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)