Arf and p53 act as guardians of a quiescent cellular state by protecting against immortalization of cells with stable genomes

► Arf is required for p53-dependent down-regulation of H2AX and cellular quiescence. ► Wild-type MEFs do not immortalize during Arf/p53-dependent quiescence. ► Tetraploidization is required for immortalization of wild-type MEFs. ► Tetraploidization is dispensable for immortalization of Arf/p53-mutated MEFs. ► Arf/p53-mutated MEFs often undergo mitotic catastrophe-associated cell death.