USP49 Participates In The DNA Damage Response By Forming A Positive Feedback Loop With P53

The p53 tumor suppressor is a critical factor in the DNA damage response(DDR).P53 protein mainly distributes in nuclear cytoplasm and specifically binds to DNA,and its activity is phosphorylated,acetylated and methylated.Due to the degradation of ubiquitin,the expression of P53 protein was maintained at a low level under physiological conditions.Under stress conditions,the expression of P53 protein was up-regulated due to the inhibition of the degradation process of ubiquitin.The degradation of proteins in cells by ubiquitin is also a strictly regulated reversible process.The regulation of deubiquitinating enzymes(DUB)is an important part of this process.There are many DUBs in cells that hydrolyze the links between the ubiquitin chains on the substrate protein.The function of protein degradation is affected by the reverse regulation of protein degradation.Using a luciferase reporter screen,we found that overexpression of USP49 could significantly activate the DNA damage response signaling pathway.It has been found that overexpression of USP49 can increase the mRNA level of p53.Investigation of the mechanism revealed that USP49 interacts with the N terminus of p53 and suppresses several types of p53 ubiquitination.Furthermore,USP49 rendered HCT116 cells more sensitive to etoposide(Eto)-induced DNA damage and was upregulated in response to several types of cell stress,including DNA damage.Remarkably,USP49 expression was regulated by p53 and USP49 in knockout mice,which are more susceptible to azoxymethane/dextran sulfate sodium(AOM/DSS)-induced colon tumors.