Abstract
The p53 tumor suppressor is a critical factor in the DNA damage response (DDR), and regulation of p53 stability has a key role in this process. In our study, we identified USP49 as a novel deubiquitinase (DUB) for p53 from a library consisting of 80 DUBs and found that USP49 has a positive effect on p53 transcriptional activity and protein stability. 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. These findings suggest that USP49 has an important role in DDR and may act as a potential tumor suppressor by forming a positive feedback loop with p53.
Highlights
The p53 tumor suppressor is a critical factor in the DNA damage response (DDR), and regulation of p53 stability has a key role in this process
P53 is essential for upregulation of USP49 mRNA and protein in response to DNA damage, which indicates that USP49 may form a positive feedback loop with p53
We found that USP49 can increase cell sensitivity to etoposide (Eto)-induced DNA damage and that USP49-knockout mice are more susceptible to colorectal cancer induced by azoxymethane/ dextran sulfate sodium (AOM/DSS)
Summary
The p53 tumor suppressor is a critical factor in the DNA damage response (DDR), and regulation of p53 stability has a key role in this process. 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 These findings suggest that USP49 has an important role in DDR and may act as a potential tumor suppressor by forming a positive feedback loop with p53. We found that USP49 can increase cell sensitivity to etoposide (Eto)-induced DNA damage and that USP49-knockout mice are more susceptible to colorectal cancer induced by azoxymethane/ dextran sulfate sodium (AOM/DSS). These findings indicate that USP49 may act as a tumor suppressor during the genesis and development of colorectal cancer
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