A nucleolar targeting signal in PML-I addresses PML to nucleolar caps in stressed or senescent cells.
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.
Condemine
Wilfried
W
CNRS/Université de Paris 7 UMR7151, Equipe labellisée par la Ligue Contre le Cancer, Hôpital St. Louis, 1 Av. C. Vellefaux 75475, Paris Cedex 10, France.
Takahashi
Yuki
Y
Le Bras
Morgane
M
de Thé
Hugues
H
D021581:Active Transport, Cell Nucleus; D000818:Animals; D045744:Cell Line, Tumor; D002466:Cell Nucleolus / Q000235:genetics / Q000378:metabolism*; D016922:Cellular Senescence; D005090:Exodeoxyribonucleases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D045586:Intranuclear Inclusion Bodies / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D019913:Nuclear Localization Signals / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D000071156:Promyelocytic Leukemia Protein; D017510:Protein Folding; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary / Q000235:genetics; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism; D013312:Stress, Physiological / Q000235:genetics / Q000378:metabolism; D040681:Structural Homology, Protein; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism
D009363:Neoplasm Proteins; D019913:Nuclear Localization Signals; D009687:Nuclear Proteins; C513293:Pml protein, mouse; D000071156:Promyelocytic Leukemia Protein; D020033:Protein Isoforms; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D025801:Ubiquitin; C070576:PML protein, human; D005090:Exodeoxyribonucleases; C020133:exodeoxyribonuclease III