A nucleolar targeting signal in PML-I addresses PML to nucleolar caps in stressed or senescent cells

• DOI: 10.1242/jcs.007492
• Publication Date: 2007-09-18T14:44:53Z
• Authors: Wilfried Condemine; Yuki Takahashi; Morgane Le Bras; Hugues de Thé
• Keywords: Protein Folding; 0303 health sciences; Skin Neoplasms; Intranuclear Inclusion Bodies; Nuclear Localization Signals; Active Transport, Cell Nucleus; Nuclear Proteins; Promyelocytic Leukemia Protein; Neoplasm Proteins; Protein Structure, Tertiary; Mice; 03 medical and health sciences; Exodeoxyribonucleases; Stress, Physiological; Structural Homology, Protein; Cell Line, Tumor; Animals; Humans; Protein Isoforms; Cell Nucleolus; Cellular Senescence; Transcription Factors

The promyelocytic leukemia (PML) tumour suppressor is the organiser of PML nuclear bodies, which are domains the precise functions of which are still disputed. We show that upon several types of stress, endogenous PML proteins form nucleolar caps and eventually engulf nucleolar components. Only two specific PML splice variants (PML-I and PML-IV) are efficiently targeted to the nucleolus and the abundant PML-I isoform is required for the targeting of endogenous PML proteins to this organelle. We identified a nucleolar targeting domain within the evolutionarily conserved C-terminus of PML-I. This domain contains a predicted exonuclease III fold essential for the targeting of the PML-I C-terminus to nucleolar fibrillar centres. Furthermore, spontaneous or oncogene retrieval-induced senescence is associated with the formation of very large PML nuclear bodies that initially contain nucleolar components. Later, poly-ubiquitin conjugates are found on the outer shell or within most of these senescence-associated PML bodies. Thus, unexpectedly, the scarcely studied PML-I isoform links PML bodies, nucleolus, senescence and proteolysis.