Missing protein explains the appearance of tumor cells in people with Mulibrey syndrome

Researchers from the Andalusian Center for Molecular Biology and Regenerative Medicine (CABIMER), in collaboration with the Swiss Institute for Experimental Cancer Research (ISREC) have studied the devices behind the higher tendency of people with Mulibrey syndrome to develop tumors. Their results highlight the important role of the protein TRIM37, whose absence explains the appearance of tumor cells.

Mulibrey syndrome is a rare disease known as it occurs in less than 5 out of every 10,000 residents. Some of these diseases usually have a very definite genetic basis. As a result, studying the molecular functions of the altered genes in patients with these diseases, as well as contributing to the discovery of new ways of diagnosis and treatment, helps us to understand the basic tools necessary for the proper development of the individual.

The disease is characterized by growth retardation, heart failure complications and liver pathologies. In addition, patients are more likely to develop certain types of tumors. The scientific literature shows that the development of this disease is associated with a lack of a gene function called TRIM37. However, the molecular role this protein plays and how inactivity leads to disease remains unresolved. This research focused specifically on how gene inactivation may contribute to tumor development in patients affected by Mulibrey syndrome.

TRIM37 is an ubiquitin ligase; a protein that is able to alter other target proteins by adding a small third protein called ubiquitin. This change can have a number of effects on the target protein: from stabilizing and promoting its function to abruptly reducing removal.

This study, led by Dr. Fernando Romero Balestra (Cabimer / US) in collaboration with a group from the Swiss Institute for Experimental Cancer Research (ISREC), with the participation of other researchers from the Andalusian Center for Molecular Biology and Regenerative Medicine (Cabimer), comprising Dr Pablo Huertas (Cabimer / US), Andrés Domínguez Calvo (Cabimer / US), and CSIC researcher Dr Rosa M. Ríos (Cabimer / CSIC), found found that cells isolated from patients with Mulibrey syndrome cannot control the number of small cell organelles called centrosomes. Centrosomes are involved in the circulation and organization of the microtubules necessary for the formation of the mitotic spindle and the proper separation of genetic material during cell division.

Healthy cells contain two centrosomes that, after cell division, are distributed between the two daughter cells, thus possessing one centrosome each. Each daughter cell, before entering the next mitosis, must construct a “new centrosome” with a complex and fully regulated molecular process that guarantees the formation of one new centrosome and ensures proper separation of chromosomes in the next mitosis.

This current study describes how cells from patients with Mulibrey syndrome, by acquiring a higher number of centrosomes, during cell division form infectious mitotic spindles that often make errors and ‘cells were generated with the wrong number of chromosomes.

Interestingly, this dysregulation of centrosome number and the associated chromosome separation problems is a feature of many tumor types. Therefore, the researchers suggest that the role of TRIM37 as a centrosome number regulator may be important in tumor formation in patients with Mulibrey syndrome.

But what molecular mechanisms bind TRIM37 with the formation of new centrosomes? To answer this question the study turns to molecular biology and cell biology techniques. To identify the mechanisms by which these new centrosomes are uncontrolledly generated in cells that do not have TRIM37, the researchers used human cell lines that are easily grown in the laboratory and, therefore, modified by Crispr / Cas9 genomic editing methods or by RNA intervention (RPE-1 and HeLa cells).

The use of these techniques has revealed how the absence of TRIM37 activates centrosome formation through a hitherto unspecified pathway of centrosome formation dependent on the Centrobin, PLK4, HsSAS-6 and PLK1 proteins. The absence of TRIM37 promotes the formation of Centrobin and PLK4 structures that are a platform for centrosome non-regulatory production.

The results of this study contribute to a better understanding of the molecular mechanisms involved in Mulibrey syndrome and open the door to the discovery of personalized treatments for patients with developing Mulibrey syndrome. tumor pathologies. In the future, the authors intend to investigate whether the molecular mechanism involved in the formation of an additional centrosome plays a key role in other tumor types.