How ribosome production and cell division rate are coupled

Electron density map of the MDM2-5S-RNP complex at different contour levels © Ed
Electron density map of the MDM2-5S-RNP complex at different contour levels © Ed Hurt Research Group.

Scientists at Heidelberg University investigate functional details of a ribonucleoprotein complex for this circuitry.

In order for cancer cells to divide continuously and unchecked, they have to outsmart the cellular mechanisms that normally ensure tight control of cell division. One of the elementary cellular processes is the production of ribosomes, which is manipulated by cancer cells in such a way that the ribosome production rate is ramped up, thus enabling the necessary high cell division rate. A research team at Heidelberg University’s Biochemistry Center has studied the large ribosomal subunit 60S, which plays a mediating role in the coupling of these two processes. The scientists were able to elucidate the structural and functional details of a ribonucleoprotein complex that controls this process.

Ribosomes are the nano-machines of the cell, which, as protein factories, produce proteins vital to the organism with various tasks. Correct ribosome production is therefore of elementary importance for cell division and cell proliferation. As biochemist Ed Hurt explains, it was first observed about 20 years ago that the division of cancer cells can be inhibited if the production of new ribosomes is blocked. It took another decade to clarify what the molecular causes of this coupling might be.

A ribonucleoprotein particle (RNP) called 5S RNP plays a crucial role in this process. In studying its properties, the Heidelberg research team led by Hurt was able to show how the components of 5S RNP interact with each other and with other cellular factors to drive ribosome assembly. However, this ribonucleoprotein particle can be pulled off the ribosomal pathway when ribosome production is impaired. In this case, the free 5S RNP binds to a specific enzyme, a ubiquitin ligase, preventing its normal function, which is to keep the tumor suppressor protein p53 the guardian of the genome low. The consequence is the growth of p53, with the consequence of a negative influence on cell division and cell proliferation.

Hurt’s research team has developed an assay that mimics how 5S RNP is incorporated into newly forming ribosomes in a test tube. Our method could be used to study how to inhibit ribosome synthesis and thus cell division in diseases such as cancer. Such approaches are important for breaking new ground in cancer treatment research and cancer drug development, emphasizes Nestor Castillo Duque de Estrada, a doctoral student in Ed Hurt’s research group who has studied these processes in detail.

The research results were obtained in collaboration with colleagues at Ludwig Maximilian University in Munich, the European Molecular Biology Laboratory in Heidelberg and the Max Planck Institute for Biophysics in Frankfurt am Main. They were funded by the German Research Foundation and the European Union. The results have been published in the journal Nature Structural & Molecular Biology.

N. M. Castillo Duque de Estrada, M. Thoms, D. Flemming, H. M. Hammaren, R. Buschauer, M. Ameismeier, J. Baßler, M. Beck, R. Beckmann, E. Hurt: Structure of nascent 5S RNPs at the crossroad between ribosome assembly and MDM2p53 pathways. In: Nature Structural & Molecular Biology (2023).