The cohesin complex is one of the latter, formed by a group of key proteins in the processes of DNA transcription and replication. These proteins are particularly important in various types of cancer and in the context of rare diseases such as Cornelia de Lange syndrome, a genetic disorder that causes, among other things, growth retardation, facial dysmorphia and limb defects.
So far, it is known that the function of the cohesin complex is to generate large loops of DNA in a controlled manner. However, little is known about its control mechanisms. Using computational simulation tools, the Molecular Modeling Group of the Severo Ochoa Molecular Biology Center (CSIC-UAM), which is dependent on the Ministry of Science, Innovation and Universities (MICIU), has for the first time proposed a latching mechanism involving the proteins STAG2 and RAD21. This mechanism allows the unidirectional elongation of DNA loops and at the same time blocks the recoil and therefore the shortening of these loops.
DNA bond formation, a key mechanism in cellular processes
In recent years, leading research groups around the world have proposed several mechanisms to explain how DNA bonds form from the structure of the cohesin complex. “Some have proposed caterpillar-like mechanisms in which proteins move onto DNA like a caterpillar on a branch.” Others propose pumping mechanisms, similar to those of a caterpillar, but without the creeping motion of the complex. Regardless of the type of procedure, all of these models would need a system to prevent the protein complex from moving backwards once it has moved the DNA forward,” the CBM researchers explain. David Ros-Pardo, Íñigo Marcos-Mayor y Paulino Gómez-Puertas. However, a system component with a locking mechanism function capable of ensuring process routing has not yet been designed.
That’s the main news of a recent study published in the journal International Journal of Biological Macromoleculeswhich suggests a role for two of the proteins in the complex, STAG2 and RAD21, to function as a safety system capable of allowing progression but not regression. “This system would act as a ratchet mechanism similar to the tab of a plastic duct tape that allows the tape of the duct tape to slide, but only in one direction,” the researchers add. The STAG2/RAD21 assembly would allow unidirectional DNA displacement, thereby facilitating loop elongation and preventing their collapse.
Computational techniques for the study of DNA
Computational dynamic molecular modeling techniques were used to perform this study, both at the atomic scale and at slightly higher scales known as “coarse” simulations. These types of approaches allow simulation times of a few microseconds in complex systems, i.e. systems that contain several proteins moving along DNA strands of more than a hundred base pairs in length. All this has been achieved thanks to high-performance computing systems, such as those located at the Scientific Computing Center of the Autonomous University of Madrid (UAM), integrated into the Spanish supercomputer network.
This study allows for the first time to understand the regulation of DNA bond formation, a key mechanism in cellular processes such as gene expression or cell division. “Very importantly, it offers insight mechanistic blocks DNA sliding and transforms STAG2 and RAD21 proteins into new potential targets for drug development,” CBM scientists explain. These drugs could be able to stop or regulate cell division as a future anti-cancer treatment or as a possible treatment for Cornelia de Lange syndrome and other related rare diseases.
Scientific reference:
Ros-Pardo, D., Gómez-Puertas, P. & Marcos-Alcalde, I. ‘STAG2-RAD21 Complex: a Unidirectional DNA Ratchet Mechanism in Loop Extrusion’. International Journal of Biological Macromolecules. 10.1016/j.ijbiomac.2024.133822
Source: CBM-CSIC
