The Mechanism Of DNMT2 Deletion Induced Cellular Senescence

DNA methyltransferase 2(DNMT2)is a member of the family of nucleic acid modifying enzymes that catalyze the transfer of methyl groups from the cofactor S-adenosylmethionine(SAM)to the fifth carbon position of cytosine residue leading to the formation of 5m C DNMT2 can act as both DNA and RNA methyltransferase.However,recent studies have found that DNMT2 is primarily a highly specific t RNAAsp methyltransferase rather than acting on DNA methylation.Cell senescence is a type of stress-induced cell cycle arrest that restricts replication of senescent and damaged cells by inhibiting cell growth.At present,aging is considered to be a stress response caused by endogenous or exogenous damage;activation of proto-oncogenes,oxidative and genotoxic stress,radiation,and chemotherapy can cause cellular aging.Cell aging is a natural barrier to tumorigenesis and it contributes to the antitumor effects of multiple therapies,including radiotherapy and chemotherapy drugs.At present,only a few studies have suggested that DNMT2 can inhibit cell senescence and prolong the lifespan of fruit flies,but the mechanism has not yet been elucidated.In this study,we found that DNMT2 knockout significantly increased the SASP(senesence-associated secret phenotype)gene expression in gastric cancer cell AGS,human fibroblast BJ,and mouse fibroblast L929,which became more prominent under the etoposide stimulation,indicating that the deletion of DNMT2 activated the senescence-related signaling pathway.Deletion of DNMT2 can inhibit the migration of gastric cancer cells and undermined the cell repair ability.We generated the DNMT2-knockout mouse and found that the growth of melanoma was inhibited in these mice.We then Kaplan-meier survival rate of cancer patients.In addition,we further studied the biological function of DNMT2 and found that the DNMT2 gene can promote the expression of foreign DNA,thereby affecting the transfection efficiency of cells.The above date suggest that DNMT2 knockout causes intracellular DNA damage response and activation of senescence-related signaling pathways,and DNMT2 may play a key role in inducing cellular senescence.It provides a better understanding of the mechanism of DNMT2 in aging and the corresponding metabolic disease or cancer treatment.