Dataset Information

Nuclear stabilization of p53 requires a functional nucleolar surveillance pathway.

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.

SUBMITTER: Hannan KM

PROVIDER: S-EPMC9647041 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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Nuclear stabilization of p53 requires a functional nucleolar surveillance pathway.

Hannan Katherine M KM Soo Priscilla P Wong Mei S MS Lee Justine K JK Hein Nadine N Poh Perlita P Wysoke Kira D KD Williams Tobias D TD Montellese Christian C Smith Lorey K LK Al-Obaidi Sheren J SJ Núñez-Villacís Lorena L Pavy Megan M He Jin-Shu JS Parsons Kate M KM Loring Karagh E KE Morrison Tess T Diesch Jeannine J Burgio Gaetan G Ferreira Rita R Feng Zhi-Ping ZP Gould Cathryn M CM Madhamshettiwar Piyush B PB Flygare Johan J Gonda Thomas J TJ Simpson Kaylene J KJ Kutay Ulrike U Pearson Richard B RB Engel Christoph C Watkins Nicholas J NJ Hannan Ross D RD George Amee J AJ

Cell reports 20221101 5

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 ...[more]

PMID: 36323262

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Project description:NOL7 is a candidate tumor suppressor that localizes to a chromosomal region 6p23. This locus is frequently lost in a number of malignancies, and consistent loss of NOL7 through loss of heterozygosity and decreased mRNA and protein expression has been observed in tumors and cell lines. Reintroduction of NOL7 into cells resulted in significant suppression of in vivo tumor growth and modulation of the angiogenic phenotype. Further, NOL7 was observed to localize to the nucleus and nucleolus of cells. However, the mechanisms regulating its subcellular localization have not been elucidated.An in vitro import assay demonstrated that NOL7 requires cytosolic machinery for active nuclear transport. Using sequence homology and prediction algorithms, four putative nuclear localization signals (NLSs) were identified. NOL7 deletion constructs and cytoplasmic pyruvate kinase (PK) fusion proteins confirmed the functionality of three of these NLSs. Site-directed mutagenesis of PK fusions and full-length NOL7 defined the minimal functional regions within each NLS. Further characterization revealed that NLS2 and NLS3 were critical for both the rate and efficiency of nuclear targeting. In addition, four basic clusters within NLS2 and NLS3 were independently capable of nucleolar targeting. The nucleolar occupancy of NOL7 revealed a complex balance of rapid nucleoplasmic shuttling but low nucleolar mobility, suggesting NOL7 may play functional roles in both compartments. In support, targeting to the nucleolar compartment was dependent on the presence of RNA, as depletion of total RNA or rRNA resulted in a nucleoplasmic shift of NOL7.These results identify the minimal sequences required for the active targeting of NOL7 to the nucleus and nucleolus. Further, this work characterizes the relative contribution of each sequence to NOL7 nuclear and nucleolar dynamics, the subnuclear constituents that participate in this targeting, and suggests a functional role for NOL7 in both compartments. Taken together, these results identify the requisite protein domains for NOL7 localization, the kinetics that drive this targeting, and suggest NOL7 may function in both the nucleus and nucleolus.

Dataset Information

Nuclear stabilization of p53 requires a functional nucleolar surveillance pathway.

Publications

Nuclear stabilization of p53 requires a functional nucleolar surveillance pathway.

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