Nuclear stabilization of p53 requires a functional nucleolar surveillance pathway.
Cell Rep
; 41(5): 111571, 2022 11 01.
Article
em En
| MEDLINE
| ID: mdl-36323262
ABSTRACT
The nucleolar surveillance pathway monitors nucleolar integrity and responds to nucleolar stress by mediating binding of ribosomal proteins to MDM2, resulting in p53 accumulation. Inappropriate pathway activation is implicated in the pathogenesis of ribosomopathies, while drugs selectively activating the pathway are in trials for cancer. Despite this, the molecular mechanism(s) regulating this process are poorly understood. Using genome-wide loss-of-function screens, we demonstrate the ribosome biogenesis axis as the most potent class of genes whose disruption stabilizes p53. Mechanistically, we identify genes critical for regulation of this pathway, including HEATR3. By selectively disabling the nucleolar surveillance pathway, we demonstrate that it is essential for the ability of all nuclear-acting stresses, including DNA damage, to induce p53 accumulation. Our data support a paradigm whereby the nucleolar surveillance pathway is the central integrator of stresses that regulate nuclear p53 abundance, ensuring that ribosome biogenesis is hardwired to cellular proliferative capacity.
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Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Proteína Supressora de Tumor p53
/
Proteínas Proto-Oncogênicas c-mdm2
Tipo de estudo:
Screening_studies
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article