Nuclear stabilization of p53 requires a functional nucleolar surveillance pathway
(2022) In Cell Reports 41(5).- 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... (More)
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.
(Less)
- author
- organization
- publishing date
- 2022
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- CP: Molecular biology, high-content screening, high-throughput screening, nucleolar surveillance pathway, nucleolus, p53, ribosomal proteins, ribosome biogenesis, stress
- in
- Cell Reports
- volume
- 41
- issue
- 5
- article number
- 111571
- publisher
- Cell Press
- external identifiers
-
- pmid:36323262
- scopus:85140875083
- ISSN
- 2211-1247
- DOI
- 10.1016/j.celrep.2022.111571
- language
- English
- LU publication?
- yes
- id
- bfdf686f-3b20-4dfa-a4d8-9db4536f7f0f
- date added to LUP
- 2022-12-13 11:17:50
- date last changed
- 2024-06-13 21:31:41
@article{bfdf686f-3b20-4dfa-a4d8-9db4536f7f0f,
abstract = {{<p>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.</p>}},
author = {{Hannan, Katherine M. and Soo, Priscilla and Wong, Mei S. and Lee, Justine K. and Hein, Nadine and Poh, Perlita and Wysoke, Kira D. and Williams, Tobias D. and Montellese, Christian and Smith, Lorey K. and Al-Obaidi, Sheren J. and Núñez-Villacís, Lorena and Pavy, Megan and He, Jin Shu and Parsons, Kate M. and Loring, Karagh E. and Morrison, Tess and Diesch, Jeannine and Burgio, Gaetan and Ferreira, Rita and Feng, Zhi Ping and Gould, Cathryn M. and Madhamshettiwar, Piyush B. and Flygare, Johan and Gonda, Thomas J. and Simpson, Kaylene J. and Kutay, Ulrike and Pearson, Richard B. and Engel, Christoph and Watkins, Nicholas J. and Hannan, Ross D. and George, Amee J.}},
issn = {{2211-1247}},
keywords = {{CP: Molecular biology; high-content screening; high-throughput screening; nucleolar surveillance pathway; nucleolus; p53; ribosomal proteins; ribosome biogenesis; stress}},
language = {{eng}},
number = {{5}},
publisher = {{Cell Press}},
series = {{Cell Reports}},
title = {{Nuclear stabilization of p53 requires a functional nucleolar surveillance pathway}},
url = {{http://dx.doi.org/10.1016/j.celrep.2022.111571}},
doi = {{10.1016/j.celrep.2022.111571}},
volume = {{41}},
year = {{2022}},
}