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How to fold your genes
Scientists have solved a longstanding puzzle of how cells are able to tightly package DNA to enable healthy cell division. Their findings shed light on how single cells can compact DNA into 10,000-folds then divide it between two identical cells - a process essential for growth, repair and maintenance of living beings. Biochemical and imaging technologies combined with sophisticated mathematical analysis, reveal the details.
They identify several processes which enable copies of DNA in an existing cell to take on the necessary structure to divide precisely into two new cells. The study clarifies one key aspect of how cells are able to constantly divide and renew, which has challenged scientists since the late 19th century. Researchers found that when cells divide, strands of genetic material are folded to form a series of compacted loops. These loops project out from a helix-shaped axis, much like steps on a spiral staircase.
A key set of proteins known as condensin II controls formation of these large loops of DNA, anchoring them to the central spiral axis. A related protein group, condensin I, pinches smaller loops within these larger coils, enabling genetic material to be compacted efficiently in preparation for cell division. This combination of a helical axis, projecting loops of DNA, along with dense packing — compresses the genome into an orderly structure that can be accurately split when cells divide.
The study pinpoints the role of condensin I and condensin II, two "molecular machines" previously known to have a key association with cell division.
Published in Science, the study was carried out by the University of Edinburgh, Scotland; the University of Massachusetts Medical School, USA; Howard Hughes Medical Institute and the Massachusetts Institute of Technology, USA, and supported by The Wellcome Trust, United Kingdom.
Professor William Earnshaw PhD, of the University of Edinburgh's Wellcome Trust Centre for Cell Biology: "This discovery reveals a fundamental, but little-understood aspect of how cells divide - a process that efficiently packages enormous lengths of DNA into an impossibly small cell nucleus. Our results are an example of how, in future, intractable scientific problems may be solved by harnessing expertise across different fields - in our case combining biological and mathematical techniques."
Dr Tom Collins PhD, from Wellcome's Genetics and Molecular Sciences team, adds: "Scientists have been grappling with the question of how cells compact their chromosomes during mitosis for close to 150 years so it is brilliant to see decades of work come to fruition. It's the beginning of a long journey towards practical applications and the next step is to take this knowledge of how the process works in healthy cells, and identify what can go wrong to cause cancer or birth defects."
Mitotic chromosomes fold as compact arrays of chromatin loops. To identify the pathway of mitotic chromosome formation, we combined imaging and Hi-C of synchronous DT40 cell cultures with polymer simulations. We show that in prophase, the interphase organization is rapidly lost in a condensin-dependent manner and arrays of consecutive 60 kb loops are formed. During prometaphase ~80 kb inner loops are nested within ~400 kb outer loops. The loop array acquires a helical arrangement with consecutive loops emanating from a central spiral-staircase condensin scaffold. The size of helical turns progressively increases during prometaphase to ~12 Mb. Acute depletion of condensin I or II shows that nested loops form by differential action of the two condensins while condensin II is required for helical winding.
Authors: Johan H. Gibcus, Kumiko Samejima, Anton Goloborodko, Itaru Samejima, Natalia Naumova, Johannes Nuebler, Masato T. Kanemaki, Linfeng Xie, James R. Paulson, William C. Earnshaw, Leonid A. Mirny, Job Dekker
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When a cells divides, strands of genetic material are folded to form a series of compacted loops,
which project out from a central, helix-shaped axis — like steps on a spiral staircase.
Smaller loops are pinched within the larger coils. Image credit: University of Edinburgh