UHRF1 overexpression generates distinct senescent states with different Tp53 dependencies

Abstract Senescence is a pleiotropic phenotype that alternatively suppresses or promotes cancer. Tumor-suppressive roles are attributed to irreversible cell cycle arrest and immune clearance, while tumor-promoting functions include apoptosis resistance and immune evasion, allowing cells to persist and support the tumor microenvironment or escape senescence and proliferate. Epigenetic changes are common features of senescent cells, and we used a preneoplastic liver cancer model caused by overexpression of the epigenetic regulator, UHRF1, in zebrafish hepatocytes to investigate how epigenome repatterning generates diverse senescent phenotypes. Early responses to UHRF1 overexpression include DNA damage, DNA methylome repatterning, retrotransposon derepression, cell cycle withdrawal, and atm and tp53 -dependent senescence. scRNAseq analysis uncovers distinct senescent cell populations, some expressing immunogenic and anti-apoptotic genes, and others expressing proliferation genes. These populations have different capacities and susceptibilities based on UHRF1 levels. Cells with low UHRF1 levels proliferate in tp53 mutants, while cells with high UHRF1 levels do not re-enter the cell cycle and are targeted by the senolytic Navitoclax. This indicates that UHRF1 expression level can generate diverse senescent cell phenotypes with divergent outcomes.