Implications of SMC Motor Behavior for Genetic and Developmental Disorders

 

A vital part of gene control, the Structural Maintenance of Chromosomes (SMC) motors are molecular engines that form DNA into loops. Genes are able to turn on or off as necessary because these motors pull far-flung sections of DNA closer together. SMC motors, on the other hand, were thought to travel unidirectionally along DNA for decades. This made elucidating how they adjust to the intricate requirements of cellular control extremely difficult.

The exact timing of gene regulation is crucial, particularly when a cell must react rapidly to changes in its surroundings, such as changes in temperature or the availability of nutrients. SMC motors work by looping DNA and joining certain regions to control gene activity. SMC motors are thought to move in a single direction and only pull DNA from one side. Because of this, the motor would not be able to fix itself if it loaded on the incorrect region of the DNA or ran into an obstruction. These restrictions would make loop construction less effective, particularly in dynamic biological contexts where quick changes in gene expression are essential.

In order to form loops, SMC motors have been discovered to travel in both directions, drawing DNA from both sides. Because of a precisely controlled switch that enables the motor to reverse direction when necessary, this process is not random. To ensure accurate loop construction, the motor may overcome barriers by switching between pulling DNA from one side and then the other. The activity of individual SMC motors interacting with single DNA molecules was observed in order to identify this bidirectional movement. With repeated direction changes, the motors were observed to gradually draw DNA into loops from both ends.

A protein subunit known as NIPBL, which functions as a gear lever, is essential to SMC motors. This subunit controls the motor's direction change, which enables it to pull DNA from either side alternatively. After engaging with a DNA segment and pulling it inside, the motor moves to the opposite side and pulls DNA from that end. Because of its activity, the motor can "explore" the DNA in both directions until it comes across particular stop signals, which guarantees that the loops are generated at the proper places. In addition to providing a sophisticated adaptation for dynamic cellular control, the motor's reversible function addresses the difficulties associated with unidirectional movement.

SMC motors' recently discovered bidirectional capability eliminates a number of restrictions. It enables them to more effectively create DNA loops in spite of loading mistakes or other barriers. This system makes sure that cells can swiftly and accurately adjust their gene regulation machinery, which is an essential ability for reacting to developmental cues, stress, and environmental changes. The bidirectional mechanism also clarifies some previously contradictory findings about SMC motors. There have been previous studies that demonstrated unidirectional movement, but others that suggested pulling DNA from both sides. By bringing these viewpoints together, our discovery provides a coherent explanation of how these motors operate in various systems.

Single SMC motors on DNA molecules might be directly observed thanks to sophisticated imaging techniques like nanometer-scale microscopy. These studies demonstrated that the NIPBL subunit coordinated the switching process as the motors pulled DNA in alternate directions. By using a high-resolution imaging technique, analysts were able to precisely identify the ways in which the motor and DNA interact, recording the dynamic movement that creates loops. Examining how SMC motor flaws contribute to illnesses is made feasible by comprehending this process.

SMC motors' ability to travel in both directions has important ramifications for our knowledge of cellular dysfunction and hereditary diseases. Improper SMC motor function has been associated with conditions like Cornelia de Lange syndrome, which shows significant developmental defects. In order to prevent diseases like cancer, these motors also contribute to the stability of the genome. It is possible to target faulty motors with new therapy approaches by figuring out how SMC motors change orientation. This information may help treat a variety of genetic and developmental diseases by restoring appropriate DNA looping and gene control.

REFERENCE:

Barth, R., Davidson, I. F., van der Torre, J., Taschner, M., Gruber, S., Peters, J. M., & Dekker, C. (2025). SMC motor proteins extrude DNA asymmetrically and can switch directions. Cell. DOI: 10.1016/j.cell.2024.12.020

IMAGE SOURCE:

https://www.labmanager.com/dna-origami-folded-into-tiny-motor-31666