The 5S RNP Couples p53 Homeostasis to Ribosome Biogenesis and Nucleolar Stress

Summary

Several proto-oncogenes and tumor suppressors regulate the production of ribosomes. Ribosome biogenesis is a major consumer of cellular energy, and defects result in p53 activation via repression of mouse double minute 2 (MDM2) homolog by the ribosomal proteins RPL5 and RPL11. Here, we report that RPL5 and RPL11 regulate p53 from the context of a ribosomal subcomplex, the 5S ribonucleoprotein particle (RNP). We provide evidence that the third component of this complex, the 5S rRNA, is critical for p53 regulation. In addition, we show that the 5S RNP is essential for the activation of p53 by p14 ^ARF, a protein that is activated by oncogene overexpression. Our data show that the abundance of the 5S RNP, and therefore p53 levels, is determined by factors regulating 5S complex formation and ribosome integration, including the tumor suppressor PICT1. The 5S RNP therefore emerges as the critical coordinator of signaling pathways that couple cell proliferation with ribosome production.

Graphical Abstract

Highlights

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  The 5S RNP (5S rRNA/RPL5/RPL11) activates p53 when ribosome production is blocked

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  The 5S RNP is required for p53 activation by the tumor suppressor p14 ^ARF

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  PICT1 controls p53 levels by regulating 5S RNP integration into the ribosome

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  Ribosome biogenesis is directly coupled to cellular proliferation via the 5S RNP

Abstract

RPL5 and RPL11 have both been shown to inhibit the ubiquitination and therefore subsequent degradation of p53 by MDM2. Sloan, Bohnsack, and Watkins report that RPL5 and RPL11, together with the 5S rRNA, regulate p53 in the context of a ribosomal subcomplex, the 5S RNP. They show that the abundance of the 5S RNP, and therefore p53 levels, are determined by factors regulating 5S complex formation and ribosome integration, including the tumor suppressor PICT1.