Menin Regulates DNA Damage Repair By The Mechanism Of Chromatin Remodeling

Radiotherapy and chemotherapy are the most commonly used methods of cancer treatment.The mechanism of their action is to induce severe DNA damage to promote the killing of tumor cells.However,the generation of radiotherapy and chemotherapy tolerance seriously affects the prognosis of patients,leading to disease recurrence and death of patients.At present,abnormal DNA damage repair is considered to be the main cause of tolerance to radiotherapy and chemotherapy.Therefore,having a good command of knowledge of the molecular mechanism of DNA damage repair in cells is helpful to inhibit DNA damage repair and enhance the sensitivity of tumor radiotherapy and chemotherapy.Menin,the coding protein of multiple endocrine tumor type 1(MEN1),a key pathogenic gene,is a multi-dimensional regulator of DNA damage repair pathway and chromatin remodeling pathway and plays an important regulatory role in DNA damage repair.However,the molecular mechanism of its action remains unclear.In this study,previous experiments showed that ionizing radiation induced menin enrichment on chromatin to regulate DNA damage repair.Subsequently,in order to explore the internal relationship between menin and DNA damage repair,the present study took Men1 knockout mouse embryonic fibroblasts as the model,and found through immunofluorescence experiments that menin deletion intensifies DNA double-strand break(DSB)induced by ionizing radiation.In order to further explore the regulation of menin on DSB repair pathway,this study confirmed by Western blot that menin deficiency abnormally activated DSB repair pathway and up-regulated protein levels of key DSB repair factors Ku80 and Rad51 as well as their chromatin recruitment.In order to explore whether menin regulates DSB repair through chromatin remodeling,the present study demonstrated that menin deficiency promotes chromatin structure opening,enhances chromatin accessibility,and thus promotes DNA damage repair by micrococcus nuclease(MNase)assay.Finally,this study confirmed that menin may regulate chromatin remodeling through ATP-dependent chromatin remodeling factor SMARCA5 and histone H3K9me3 modification.In this paper,menin-mediated DNA damage repair is the starting point,focusing on the molecular mechanism of menin regulating chromatin remodeling,and determining the important role of menin in chromatin remodeling and DNA damage repair pathways.The target research and development of tumor radiotherapy and chemotherapy sensitizers provides a new theoretical basis.