Heidelberg University researchers examine functional details of a ribonucleoprotein complex for this link
For cancer cells to proliferate constantly and unchecked, they have to outwit the cellular mechanisms that normally ensure the strict control of cell division. One of the elementary cellular processes involved is the production of ribosomes, which cancer cells manipulate to ramp up production and thereby allow the high division rates needed. A research team at the Biochemistry Center of Heidelberg University investigated the large ribosomal subunit 60S, which plays a mediator role in linking these two processes. The researchers were able to explain the structural and functional details of a ribonucleoprotein complex that controls this process.
Ribosomes are the nanomachines of the cell. They act as protein factories for the organism, producing vital proteins with various tasks. Correct ribosomal formation is therefore of elementary importance in cell division and propagation. As biochemist Prof. Dr Ed Hurt explains, scientists first observed about 20 years ago that cancer cell division could be inhibited by blocking the production of new ribosomes. It took another decade until they were able explain what the molecular origins of this connection might be.
A ribonucleoprotein particle (RNP) called 5S RNP plays a critical role in this association. While studying its properties, the Heidelberg research team led by Prof. Hurt was able to reveal how 5S RNP components interacted with each other and other cellular factors to drive ribosome assembly. If ribosome production is disturbed, however, this ribonucleoprotein can be “pulled” from the ribosomal pathway. In this case, free 5S RNP binds to a certain enzyme, a ubiquitin ligase, and thereby blocks its normal function, namely repressing the tumour-suppressing protein p53, the "guardian of the genome". This causes p53 to pool, negatively influencing cell division and proliferation.
Prof. Hurt's research team developed a test that imitates, in a test tube, how 5S RNP is incorporated into the newly formed ribosomes. "Our process could be used to study how ribosome synthesis and hence cell division could be inhibited in illnesses such as cancer. Such approaches are important to break new ground in cancer treatment research and the development of cancer medications", stresses Nestor Castillo Duque de Estrada, a doctoral candidate in Prof. Hurt's research group who investigated these processes in detail.
The research results were produced in collaboration with colleagues from Ludwig Maximilian University of Munich, the European Molecular Biology Laboratory in Heidelberg, and the Max Planck Institute for Biophysics in Frankfurt am Main. The German Research Foundation and the European Union provided the funding. The results of the research were published in “Nature Structural & Molecular Biology”.
Original Publication 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 MDM2–p53 pathways. In: Nature Structural & Molecular Biology (2023).