Nuclear stabilization of p53 requires a functional nucleolar surveillance pathway

Hannan, KM; Soo, P; Wong, MS; Lee, JK; Hein, N; Poh, P; Wysoke, KD; Williams, TD; Montellese, C; Smith, LK; Al-Obaidi, SJ; Nunez-Villacis, L; Pavy, M; He, JS; Parsons, KM; Loring, KE; Morrison, T; Diesch, J; Burgio, G; Ferreira, R; Feng, ZP; Gould, CM; Madhamshettiwar, PB; Flygare, J; Gonda, TJ; Simpson, KJ; Kutay, U; Pearson, RB; Engel, C; Watkins, NJ; Hannan, RD; George, AJ

Author(s): Hannan, KM; Soo, P; Wong, MS; Lee, JK; Hein, N; Poh, P; Wysoke, KD; Williams, TD; Montellese, C; Smith, LK; Al-Obaidi, SJ; Nunez-Villacis, L; Pavy, M; He, JS; Parsons, KM; Loring, KE; Morrison, T; Diesch, J; Burgio, G; Ferreira, R; Feng, ZP; Gould, CM; Madhamshettiwar, PB; Flygare, J; Gonda, TJ; Simpson, KJ; Kutay, U; Pearson, RB; Engel, C; Watkins, NJ; Hannan, RD; George, AJ;
Details: Publication Year 2022-11-01,Volume 41,Issue #5,Page 111571
Journal Title: Cell Reports
Publication Type: Research article
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.
Keywords: *Tumor Suppressor Protein p53/genetics/metabolism; *Proto-Oncogene Proteins c-mdm2/genetics/metabolism; Signal Transduction/genetics; Cell Nucleolus/metabolism; Ribosomal Proteins/genetics/metabolism; CP: Molecular biology; high-content screening; high-throughput screening; nucleolar surveillance pathway; nucleolus; p53; ribosomal proteins; ribosome biogenesis; stress
Department(s): Laboratory Research
PubMed ID: 36323262
Publisher's Version: https://doi.org/10.1016/j.celrep.2022.111571
Open Access at Publisher's Site: https://doi.org/10.1016/j.celrep.2022.111571
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2024-11-01 04:13:51

Last Modified: 2024-11-01 06:39:06