NOL12 Repression Induces Nucleolar Stress-Driven Cellular Senescence and Is Associated with Normative Aging

The nucleolus is a subnuclear compartment with key roles in rRNA synthesis and ribosome biogenesis, complex processes that require hundreds of proteins and factors. Alterations in nucleolar morphology and protein content have been linked to the control of cell proliferation and stress responses and,...

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Bibliographic Details
Published in:Molecular and cellular biology 2019-06, Vol.39 (12)
Main Authors: Pinho, Marta, Macedo, Joana C., Logarinho, Elsa, Pereira, Paulo S.
Format: Article
Language:English
Subjects:
Aging - genetics
Aging - metabolism
Cell Cycle Checkpoints
Cell Nucleolus - genetics
Cell Nucleolus - metabolism
Cells, Cultured
Cellular Senescence
Down-Regulation
Fibroblasts - cytology
Fibroblasts - metabolism
Homeostasis
Humans
Male
NOL12
Nuclear Proteins - genetics
Nuclear Proteins - metabolism
nucleolar stress
Ribosomal Proteins - metabolism
RNA-Binding Proteins - genetics
RNA-Binding Proteins - metabolism
senescence
Tumor Suppressor Protein p53 - metabolism
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Summary:The nucleolus is a subnuclear compartment with key roles in rRNA synthesis and ribosome biogenesis, complex processes that require hundreds of proteins and factors. Alterations in nucleolar morphology and protein content have been linked to the control of cell proliferation and stress responses and, recently, further implicated in cell senescence and ageing. In this study, we report the functional role of NOL12 in the nucleolar homeostasis of human primary fibroblasts. NOL12 repression induces specific changes in nucleolar morphology, with increased nucleolar area but reduced nucleolar number, along with nucleolar accumulation and increased levels of fibrillarin and nucleolin. Moreover, NOL12 repression leads to stabilization and activation of p53 in an RPL11-dependent manner, which arrests cells at G 2 phase and ultimately leads to senescence. Importantly, we found NOL12 repression in association with nucleolar stress-like responses in human fibroblasts from elderly donors, disclosing it as a biomarker in human chronological aging.
ISSN:1098-5549
0270-7306
1098-5549
DOI:10.1128/MCB.00099-19