Inhibition of Ribosome Biogenesis In Vivo Causes p53-Dependent Death and p53-Independent Dysfunction

Although it is well-known that ribosomes are critical for cell function, and their synthesis (known as ribosome biogenesis [RiBi]) is energy-intensive, surprisingly little is known about RiBi in vivo in adult tissue.

Using a mouse model with conditional deletion of Nat10, an essential gene for RiBi and subsequent translation of mRNA, we investigated the effects of RiBi blockade in vivo, with a focus on pancreatic acinar cells during homeostasis and tumorigenesis.

We observed an unexpected latency of several weeks between Nat10 deletion and onset of structural and functional abnormalities and p53-dependent acinar cell death. Although deletion of Trp53 rescued acinar cells from apoptotic cell death, Nat10^Δ/Δ; Trp53^Δ/Δ acinar cells remained morphologically and functionally abnormal. Deletion of Nat10 in acinar cells blocked Kras-oncogene-driven pancreatic ductal adenocarcinoma, regardless of Trp53 mutation status.

Together, our results provide initial insights into how differentiated cells respond to defects in RiBi and translation in vivo in various physiological contexts.