Defects in 18 S or 28 S rRNA processing activate the p53 pathway

Area of Science:

• Cell Biology
• Molecular Biology
• Cancer Research

Background:

• The p53 tumor suppressor pathway is crucial for cellular response to stress, including defective ribosome synthesis.
• Ribosomal protein release from the nucleolus inhibits Hdm2, preventing p53 degradation.
• The specific mechanisms by which individual rRNA processing defects stabilize p53 were not fully understood.

Purpose of the Study:

• To investigate how the abrogation of specific rRNA processing pathways contributes to p53 stabilization.
• To identify novel factors involved in rRNA processing and their link to p53.
• To elucidate the independent monitoring of small (18S) and large (28S) ribosomal RNA (rRNA) maturation by the p53 pathway.

Main Methods:

• Selective inhibition of 18S rRNA processing pathways.
• Knockdown of the novel mammalian rRNA processing factor, hUTP18.
• Analysis of p53 accumulation and its dependence on ribosomal protein L11.
• Assessment of 28S rRNA maturation in hUTP18-depleted cells.

Main Results:

• Selective inhibition of 18S rRNA processing effectively stabilizes p53, similar to 28S rRNA defects.
• hUTP18 was identified as a novel factor essential for 18S rRNA processing, specifically for cleaving the 5'-external transcribed spacer.
• hUTP18 depletion did not affect 28S rRNA maturation, indicating independent monitoring of both pathways.
• p53 stabilization upon hUTP18 knockdown was dependent on the ribosomal protein L11.

Conclusions:

• The p53 pathway can independently monitor the integrity of both 18S and 28S rRNA synthesis.
• hUTP18 plays a specific role in 18S rRNA maturation, linking its processing to p53 stabilization.
• Separate molecular routes likely monitor small and large ribosomal subunit maturation, converging in an L11-dependent pathway for p53 activation.