How Does Two-Meter DNA Fold Inside a Tiny Nucleus? Discovery of the 'Second Principle' [Reading Science]

Discovery of Energy-Independent 'Bridging' Mechanism in Addition to ATP-Driven 'Loop Extrusion'

A Newly Proposed Principle of Chromosome Organization Conserved from Yeast to Humans

If the DNA contained within a single human cell were stretched out in a line, its length would reach about two meters. Another mechanism has now been revealed that explains how this long DNA is intricately folded inside a cell nucleus with a diameter of only about 10 micrometers. Unlike the traditional mechanism that forms loops in the DNA by consuming energy, this mechanism involves proteins "bridging" between strands of DNA, gathering multiple strands together.

On September 10, Seoul National University announced that a research team led by Professor Ryu Jaekyung from the Department of Physics and Astronomy and Jaewon Jang, a researcher in the Computational Science Interdisciplinary Program, in collaboration with researchers from the Francis Crick Institute in the UK, Delft University of Technology in the Netherlands, Kyoto University in Japan, and the Korea Advanced Institute of Science and Technology (KAIST), had identified a newly conserved principle of chromosome organization common to all eukaryotes. Researcher Jang and Professor Ryu served as co–first authors, with Professor Ryu also serving as corresponding author. The results were published in the international journal Nucleic Acids Research.

The process of chromosome formation through 'DNA bridging' by SMC proteins. Cohesin and condensin connect separate DNA strands, and as this process repeats, the DNA gathers in one place to form a condensed structure. Provided by the research team

The way DNA folds is not simply a matter of fitting long genetic material into a confined space. As genes that are far apart on the DNA strand and their regulatory elements come into contact through folding, genes can be switched on or off. If this structure is disrupted, gene regulation can go awry, potentially leading to developmental disorders or cancer.

The “SMC protein complex,” typified by cohesin and condensin, plays a central role in folding chromosomes. Over the past decade, the primary working principle of SMC complexes has been described as “loop extrusion,” where ATP is used as an energy source to draw in DNA and progressively enlarge the loops.

However, this mechanism alone could not fully explain how multiple DNA loops are gathered together or how chromosomes in mitosis become short and tightly condensed.

DNA Clustered Without ATP... Discovery of 'Bridging'

The research team used single-molecule fluorescence imaging to observe four types of SMC complexes, including cohesin and condensin derived from budding yeast, fission yeast, and humans. The results showed that all four types were able to gather DNA into a condensate even in the absence of ATP. For human cohesin, condensation occurred within approximately 22 seconds, regardless of whether ATP was present or not.

Atomic force microscopy (AFM) revealed that a single cohesin molecule could simultaneously grasp two DNA strands. The process involves a single protein bridging two separate DNA segments; as surrounding DNA is drawn in, new bridges are formed, resulting in the growth of the condensate. The research team has termed this process “bridging-induced phase separation (BIPS).”

Supporting evidence for this process was also found in human cells. Super-resolution microscopy revealed that cohesin does not distribute evenly throughout the nucleus but instead forms clusters roughly 90 nanometers in diameter. High-resolution chromosome contact maps (Micro-C) showed that 15 to 25 DNA loops are overlapped within a single chromosome region.

Based on these findings, the research team proposed that SMC proteins organize chromosomes by using both “loop extrusion,” which requires ATP, and “bridging-induced condensation,” which does not consume extra energy. The observation that this phenomenon occurs from yeast to humans suggests that this chromosome organization method has been conserved across all eukaryotes.

This research is also expected to provide clues for understanding the molecular mechanisms underlying congenital developmental diseases and cancers associated with defects in cohesin and condensin.

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