Role Of SENP3 Phosphorylation In Maintaining Genomic Stability And Regulating Innate Immunity In Tumor Cells

The main purpose of mitosis is to distribute sister chromatids into progeny cells.In this process,correct separation of sister chromatids is the key to ensure correct division and proliferation of cells.The entire process of mitosis is finely regulated and during which post-translational modifications(PTMs)extensively participate in it,such as phosphorylation and ubiquitination.In addition,our laboratory and others found that SUMO modification is also involved in the regulation of mitotic progression.external factors or the disorder of self-regulation during mitosis may cause mis-separation of chromatids and induce chromatin instability,which would cause abnormal cell division and is therefore closely related to tumor development.Recent studies have shown that chromosomal instability can also cause micronucleus production.Micronuclei produced by cells can activate innate immunity through c GAS/STING signaling pathway.c GAS is the most important protein on detecting cytosolic DNA.It can recognize double-stranded DNA or DNA-RNA dimers and synthesize a second messenger c GAMP,activate the downstream receptor STING,and then promote expression of type I interferon and other inflammatory factors through IRF3 or NF-κB signaling pathway.Previous experiments in our laboratory showed that the Sentrin-specific protease SENP3 was phosphorylated by CDK1 in G2/M phase of mitosis.Phosphorylation of SENP3 can inhibit the de-SUMO enzyme activity of SENP3 and is an important for the correct separation of sister chromatids during mitosis.Mutation of the SENP3 phosphorylation sites would enhance its de-SUMO enzyme activity,cause chromatin instability,and promote tumorigenesis.We also found that DNA damage can inhibit SENP3 phosphorylation through p53-mediated pathway,which leads to G2arrest through the APC/Cdh1 pathway.But whether this regulatory mechanism involve in DNA damage induced innate immune response is unknown.In this study,we found that when tumor cells expressing mutant of SENP3 phosphorylation sites were implanted in C57BL/6 mice in which the immune system is intact,the tumor growth were significantly smaller than that expressing wild type SENP3,which is opposite to the results in nude mice.We analyed immune cells in the tumor microenvironment and found that infiltration of CD8~+T cells were significantly increased in tumors expressing mutant of SENP3 phosphorylation sites,indicating that SENP3 de-phosphorylation may inhibited tumor growth through inducing immune response.We further found that micronuclei in tumor cells expressing mutant of SENP3 phosphorylation sites significantly increased,which activated c GAS-STING signaling pathway-mediated natural immune response.through analyzing the pancreatic cancer database,we found that expression of SENP3 is positively related to the survival of patients with pancreatic cancer,and expression of SENP3 is positively related to expression of gene sets involved in inflammation and immune response.These studies indicate that SENP3phosphorylation play important role in regulating chromosome stability during mitosis.abnormal regulation of SENP3 phosphorylation can lead to generation of micronuclei and promote c GAS-STING mediated immune response.This regulatory mechanism may serve as a theoretical basis for the combined application of radiotherapy/chemotherapy with anti-PD-1 immunotherapy.