Genetic perturbation of MAPK11 (p38β) promotes radiosensitivity by enhancing IR-associated senescence

Background and purpose MAPKs are among the most relevant signalling pathways involved in coordinating cell responses to different stimuli. In this group we can find p38MAPK, constituted by 4 different proteins with a high sequence homology: p38α, p38β, p38γ and p38δ. Despite the high homology, each member shows unique expression patterns and even exclusive functions. Thus, analysing protein-specific functions of MAPK members is necessary to unequivocally uncover the roles of this signalling pathway. Here, we propose to investigate the possible role of p38β (MAPK11) in the cell response to ionizing radiation (IR). Materials and methods We have developed MAPK11/14 knockdown through shRNA and CRISPR interference gene perturbation approaches, and analysed the implication of this MAPKs in cell response to ionizing radiation in A549, HCT-116 and MCF-7 cancer cell lines. Specifically, we analysed IR toxicity by clonogenic assays; DNA damage response activity by immunocytochemistry; apoptosis and cell cycle by flow cytometry (Annexin V and propidium iodide, respectively); DNA repair by comet assay; and senescence induction by both X-Gal staining and gene expression of senescence-associated genes by RT-qPCR. Results Our findings demonstrate a critical role of MAPK11 in the cellular response to IR by controlling the associated senescent phenotype, and without observable effects on DDR, apoptosis, cell cycle or DNA damage repair Conclusion Our results highlight MAPK11 as a novel mediator of the cellular response to ionising radiation through the control exerted onto IR-associated senescence. ### Competing Interest Statement The authors have declared no competing interest. * DDR : DNA damage response DSB : Double strand break gRNA : Guide RNA IR : Ionizing radiation MAPK : Mitogen Activated Protein Kinase RT-qPCR : Quantitative real-time PCR S.D. : Standard deviation SF : Surviving fraction shRNA : short hairpin RNA