Fig. 9: Model of SURF2 function in free 5S RNP regulation.

Schematic representation of free 5S regulation by SURF2 in different conditions. a In normal cells, both 5S and 47S rDNAs are transcribed by RNA polymerase III and I, respectively. Ribosome synthesis is producing pre-60S ribosomes and 5S particles constituted by the association of RPL5 and RPL11 to 5S rRNA are incorporated into these large pre-ribosomes. The remaining overproduced free 5S are bound by SURF2 to avoid MDM2-Free 5S interaction, which would induce p53 stabilization and cell cycle arrest. At the same time, p53 is constantly ubiquitinated by MDM2 to promote its degradation by the proteasome. b After nucleolar stress (drug-induced or caused by genetic mutations/ribosomopathies), ribosome synthesis is impaired, and a larger amount of free 5S particles accumulate in the nucleoplasm. The extra free 5S particles can then be recognized by MDM2, which can no longer ubiquitinylate p53, thereby stabilizing p53 and promoting cell cycle arrest. c In cells lacking SURF2, nucleolar stress still impairs ribosome synthesis, but this time, even more, free 5S RNPs are able to bind to MDM2, inducing stronger stabilization and activation of p53, followed by more cell cycle arrest. d In contrast, in cells overexpressing SURF2, nucleolar stress promotes free 5S RNP accumulation in the nucleoplasm, all of which are recognized by SURF2, which competes with MDM2 for binding. As a result, MDM2 is free and ubiquitinylates p53, conferring to these cells a capacity to resist to nucleolar stress.