SENP1 Is a Crucial Regulator for Cell Senescence through DeSUMOylation of Bmi1

Cell senescence can limit proliferative potential and prevent tumorigenesis. Bmi1 is a key regulator in cell senescence by suppressing the Ink4a/Arf locus. However, how to regulate Bmi1 activity in cell senescence is largely unknown. Here, we show that SENP1 plays an important role in cell senescence by regulating Bmi1 SUMOylation. Senp1(-/-) primary MEF cells show resistance to cell senescence induced by passaging or other senescence inducing signals. SENP1 deficiency also reduces oncogene H-Ras(V12)-induced senescence, and enhances H-Ras(V12)-induced cell transformation. We further show that in Senp1(-/-) MEFs the expression of p19(Arf), an important regulator in p53/p21-mediated cell senescence, is markedly reduced. Meanwhile, we demonstrate that SENP1 can specifically de-SUMOylate Bmi1 and thereby decreases the occupancy of Bmi1 on p19(Arf) promoter leading to decrease of H2AK119 mono-ubiquitination and up-expression of p19(Arf). These data reveal a crucial role of SENP1 in regulation of cell senescence as well as cell transformation.