ACRF Department of Cancer Biology and Therapeutics and Division of Genome Sciences and Cancer, John Curtin School of Medical Research, Australian National University, Acton, ACT 2601, Australia; Division of Research, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, VIC 3010, Australia.
ACRF Department of Cancer Biology and Therapeutics and Division of Genome Sciences and Cancer, John Curtin School of Medical Research, Australian National University, Acton, ACT 2601, Australia.
Cell Rep. 2022 Nov 1;41(5):111571. doi: 10.1016/j.celrep.2022.111571.
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.
核仁监测途径监测核仁的完整性，并通过介导核糖体蛋白与 MDM2 的结合来响应核仁应激，从而导致 p53 的积累。该途径的异常激活与核糖体病的发病机制有关，而选择性激活该途径的药物正在进行癌症临床试验。尽管如此，调节这一过程的分子机制仍知之甚少。通过全基因组功能丧失筛选，我们证明核糖体生物发生轴是最有效的基因类别之一，其破坏可稳定 p53。从机制上讲，我们确定了调控这一途径的关键基因，包括 HEATR3。通过选择性地使核仁监测途径失活，我们证明它对于所有核作用应激（包括 DNA 损伤）诱导 p53 积累的能力是必不可少的。我们的数据支持这样一种模式，即核仁监测途径是调节核内 p53 丰度的应激的中央整合者，确保核糖体生物发生与细胞增殖能力紧密相连。
