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

ABSTRACT

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 G₂ 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.

KEYWORDS:

• NOL12
• nucleolar stress
• senescence
• p53

SUPPLEMENTAL MATERIAL

Supplemental material for this article may be found at https://doi.org/10.1128/MCB.00099-19.

ACKNOWLEDGMENTS

We acknowledge technical support from the BioSciences Screening and Histology and Electron Microscopy i3S Scientific Platforms, granted by the Portuguese Platform of Bioimaging (PPBI-POCI-01-0145-FEDER-022122).

E.L. holds an FCT Investigator grant, and M.P. holds an FCT Fellowship (SFRH/BD/110668), both from FCT/MCTES (Fundação para a Ciência e a Tecnologia/Ministério da Ciência, Tecnologia e Ensino Superior). The following project grants supported this work: Norte-01-0145-FEDER-000029 supported by North Portugal Regional Operational Programme (NORTE 2020) under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (FEDER); National Funds through FCT under project PTDC/BEX-BCM/2090/2014; European Regional Development Fund (FEDER) through the COMPETE 2020—Operational Program for Competitiveness and Internationalization (POCI), Portugal 2020, and National funds through FCT in the framework of project POCI-01-0145-FEDER-031120 (PTDC/BIA-CEL/31120/2017); and POCI-01-0145-FEDER-007274 i3S framework project cofunded by COMPETE 2020/PORTUGAL 2020 and by FCT.