Cell and Tissue BiologyCell and Tissue BiologyЦитология0041-37713034-6061The Russian Academy of Sciences66966610.31857/S0041377123010030GOTCEBArticlesСтатьиThe Role of MAP Kinases in the Induced Histone H2AX Phosphorylation in Transformed CellsРоль MAP-киназ в индуцированном фосфорилировании гистона H2AX в трансформированных клеткахGnedinaO. O.ГнединаО. О.marie.igotti@gmail.comMorshnevaA. V.МоршневаА. В.marie.igotti@gmail.comIgottiM. V.ИготтиМ. В.marie.igotti@gmail.comInstitute of Cytology, Russian Academy of SciencesИнститут цитологии РАН01012023651546327022025Copyright ©; 2023, О.О. Гнедина, А.В. Моршнева, М.В. ИготтиCopyright ©; 2023, О.О. Гнедина, А.В. Моршнева, М.В. Иготти2023О.О. Гнедина, А.В. Моршнева, М.В. ИготтиО.О. Гнедина, А.В. Моршнева, М.В. Иготтиhttps://journals.eco-vector.com/0041-3771/article/view/669666

Previously, we have shown that inhibitors of histone deacetylases (HDIs) do not induce DNA double strand breaks (DNA DSBs). However, like genotoxic agents, HDIs initiate the accumulation of phosphorylated histone H2AX (γH2AX), which is a DNA DSB marker. HDIs can also reduce the efficiency of repair of DNA damaged by genotoxic effects in transformed cells. The aim of this work was to identify the signaling pathways leading to the accumulation of γH2AX under the HDIs treatment in transformed cells. There was considered the role of the MAPK family kinases in phosphorylation of histone H2AX as well as inhibition of DNA repair induced with HDI sodium butyrate (NaBut). It was shown that the accumulation of γH2AX under the NaBut treatment is accompanied by a decrease of the ERK and PKB/Akt kinases phosphorylation level in transformed cells. The activating phosphorylation of p38 kinase increases under the NaBut treatment, causing Wip1 phosphatase accumulation, which may be one of the reasons for the DNA repair inhibition. Suppression of p38 kinase activity abolishes the NaBut-induced inhibition of repair efficiency. The data obtained suggest the role of the p38/Wip1 pathway in the HDIs-induced decrease in repair efficiency in transformed cells.

Ингибиторы гистондеацетилаз (ИГД) обладают антипролиферативными свойствами и являются перспективными агентами комбинированной противоопухолевой терапии. Ранее нами было показано, что представитель семейства ИГД бутират натрия (NaBut) самостоятельно не вызывает двунитевых разрывов ДНК (ДР-ДНК), однако, подобно генотоксическим агентам, инициирует накопление фосфорилированного гистона H2AX (γH2AX), являющегося маркером ДР-ДНК. ИГД способны также снижать эффективность репарации ДНК, поврежденной при генотоксических воздействиях, в трансформированных клетках. Цель настоящей работы состояла в идентификации сигнальных путей, приводящих к накоплению γH2AX при действии ИГД в трансформированных клетках. Для этого исследовали роль киназ семейства MAPK в NaBut-индуцированном фосфорилировании гистона H2AX, а также в ингибировании репарации ДНК. Мы показали, что накопление γH2AX в трансформированных клетках в ответ на действие NaBut сопровождается снижением уровня фосфорилирования киназ ERK и PKB/Akt. Активирующее фосфорилирование киназы р38 увеличивается при действии NaBut, вследствие чего накапливается фосфатаза Wip1, что может быть одной из причин ингибирования репарации ДНК. При этом подавление активности киназы p38 отменяет NaBut-индуцированное снижение эффективности репарации. Полученные нами результаты об отмене негативного влияния NaBut на репарацию ДНК при ингибировании MAP-киназы p38, а также данные о накоплении фосфатазы Wip1 при действии NaBut позволяют предположить, что путь p38/Wip1 вовлечен в NaBut-индуцированное снижение эффективности репарации в трансформированных клетках.

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