Inspired by this original hypothesis, a novel pathomechanism has been proposed recently in CS cells, in which an abnormal RNA polymerase I (RNA pol I) transcription activity was shown to affect ribosomal performance, inducing both misfolded proteins (Alupei et al., 2018; Qiang et al., 2021) and nucleolar stress, with the latter characterized by a p53-regulated cell cycle arrest and senescence and/or apoptosis. The gene discussed is TP53; the disease is Cowden syndrome 1.