Study uncovers a new mechanism of DNA folding

April 19, 2023

(Nanowerk News) A hitherto unknown DNA folding mechanism was described in a study in Natural (“The Smc5/6 complex is a DNA loop extrusion motor”) was published by researchers from the Karolinska Institutet and the Max Planck Institute for Biophysics. Their findings provide new insights into chromosomal processes that are important for normal development and for preventing disease.

The DNA in our cells is organized into chromosomes, which are highly dynamic structures that change when genes are transcribed, when DNA damage is repaired, or when chromosomes are condensed in preparation for cell division. These processes are influenced by the so-called SMC protein complex (SMC, Structural Maintenance of Chromosomes), which by mediating chromosomal interactions ensures the correct spatial organization of the genome.

In humans and other eukaryotes, that is, organisms whose cells contain a nucleus, three such protein complexes exist. Scientists have uncovered the mechanism by which two of them function. In this study, researchers investigated a third, the Smc5/6 complex, whose function is largely unknown.

“These results reveal the Smc5/6 complex as a novel regulator of DNA folding, which can tell us more about how chromosomes are arranged,” said Camilla Björkegren, professor in the Department of Cell and Molecular Biology at Karolinska Institutet, who led the research. along with Eugene Kim, research group leader at the Max Planck Institute for Biophysics in Frankfurt am Main. “This discovery is also of medical relevance, as DNA folding is important for normal chromosomal function and for avoiding chromosomal changes that can lead to disease.”

Researchers have purified the Smc5/6 complex from yeast and, using high-resolution microscopy of individual molecules, have studied how it binds to and affects individual DNA molecules. The principles of chromosome organization are believed to be generally identical in yeast and humans, which are both eukaryotic organisms. For their experiments, the researchers labeled both protein complexes and DNA with different colored fluorescent molecules so they could be tracked through a microscope.

Their results show that the Smc5/6 complex operates by extruding progressively larger DNA loops, a property shared with other known eukaryotic SMC complexes.

Researchers have also investigated how the process is regulated and found, among other things, that two Smc5/6 complexes are required to form a loop, whereas a single protein complex only translocates along the DNA molecule.

Previous research has shown that Smc5/6 inhibits certain viruses and suggests that it also protects against certain types of cancer, and is important for normal fetal development. The KI researchers now want to study how these properties relate to the newly discovered mechanism.

“The next step of our research is to find out how the ability of the Smc5/6 complex to create DNA loops influences its function in cells, which may enhance our understanding of how Smc5/6 may function as a viral blocker, protect against cancer, and contribute to fetal development.” said Professor Björkegren.

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