Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Active Transport, Cell Nucleus
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Animals
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Cell Line, Tumor
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Cell Nucleolus / genetics
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Cell Nucleolus / metabolism*
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Cellular Senescence*
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Exodeoxyribonucleases / genetics
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Exodeoxyribonucleases / metabolism
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Humans
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Intranuclear Inclusion Bodies / genetics
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Intranuclear Inclusion Bodies / metabolism*
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Mice
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Neoplasm Proteins / genetics
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Neoplasm Proteins / metabolism*
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Nuclear Localization Signals / genetics
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Nuclear Localization Signals / metabolism*
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Promyelocytic Leukemia Protein
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Protein Folding
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Protein Isoforms / genetics
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Protein Isoforms / metabolism
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Protein Structure, Tertiary / genetics
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Skin Neoplasms / genetics
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Skin Neoplasms / metabolism
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Stress, Physiological / genetics
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Stress, Physiological / metabolism
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Structural Homology, Protein
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism*
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Ubiquitin / genetics
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Ubiquitin / metabolism
Substances
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Neoplasm Proteins
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Nuclear Localization Signals
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Nuclear Proteins
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Pml protein, mouse
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Promyelocytic Leukemia Protein
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Protein Isoforms
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Transcription Factors
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Tumor Suppressor Proteins
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Ubiquitin
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PML protein, human
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Exodeoxyribonucleases
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exodeoxyribonuclease III