Nuclear stabilization of p53 requires a functional nucleolar surveillance pathway

• DOI: 10.1016/j.celrep.2022.111571
• Publication Date: 2022-11-01T10:44:09Z
• Authors: Katherine M. Hannan; Priscilla Soo; Mei S. Wong; Justine K. Lee; Nadine Hein; Perlita Poh; Kira D. Wysoke; Tobias D. Williams; Christian Montellese; Lorey K. Smith; Sheren J. Al-Obaidi; Lorena Núñez-Vill...; Megan Pavy; Jin-Shu He; Kate M. Parsons; Karagh E. Loring; Tess Morrison; Jeannine Diesch; Gaetan Burgio; Rita Ferreira; Zhi-Ping Feng; Cathryn M. Gould; Piyush B. Madhams...; Johan Flygare; Thomas J. Gonda; Kaylene J. Simpson; Ulrike Kutay; Richard B. Pearson; Christoph Engel; Nicholas J. Watkins; Ross D. Hannan; Amee J. George
• Keywords: Nuclear export signal

The nucleolar surveillance pathway monitors integrity and responds to stress by mediating binding of ribosomal proteins MDM2, resulting in p53 accumulation. Inappropriate activation is implicated the pathogenesis ribosomopathies, while drugs selectively activating are trials for cancer. Despite this, molecular mechanism(s) regulating this process poorly understood. Using genome-wide loss-of-function screens, we demonstrate ribosome biogenesis axis as most potent class genes whose disruption stabilizes p53. Mechanistically, identify critical regulation pathway, including HEATR3. By disabling that it essential ability all nuclear-acting stresses, DNA damage, induce Our data support a paradigm whereby central integrator stresses regulate nuclear abundance, ensuring hardwired cellular proliferative capacity.