Loops, loops, loops...How cells tidy up their DNA
One big question, debated amongst scientists for decades, is about how a cell compacts and evenly divides its DNA when dividing.
Scientist from Delft University now got the answer: Loop Extrusion
This process itself was already observed under a microscope in 1882.
That question is now firmly answered by new experiments by scientists from the Kavli Institute of Delft University and EMBL Heidelberg: the key is ‘loop extrusion’, a process that condenses DNA by pulling it in many tiny loops.
There were two theories: one states that condensin works like a hook that can grasp somewhere in the jumble of DNA, thus tying it together. An alternative proposal suggests that the ring-shaped condensin pulls the DNA inwards to create a loop.
However, in 2017, the tide shifted...
Motor FunctionMotor Function
By attaching a fluorescent molecule (starting at the red arrow in this movie) to condensin, the researchers could observe how it actually moved over DNA. The protein did so making rather large steps over the DNA molecule, which made the energy consumption of the process much more in-line with observations. That was a big clue, but…
.... as Prof. Kim Nasmyth from Oxford University—one of the leading scientists that has studied DNA organization for many years—noted in the accompanying perspective in Science:
“the discovery that condensin is a DNA translocase is certainly consistent with the idea that it functions as a loop extruder, but by no means proves it. The challenge will be to observe extrusion as well as translocation, to establish whether it is a property of individual or multimeric complexes, and to elucidate the molecular mechanism.”
In collaboration with scientists of the Christian Haering group from EMBL Heidelberg who established the purification and fluorescence labeling of the protein, they managed to make actual movies that caught the action of the condensin complex in the act.
now with flow
To his surprise, Ganji could see (and even film) a condensin protein attach itself to the DNA, where it started extruding a very long loop of DNA...
Side by Side
Surprisingly, the loop extrusion is asymmetric: condensin is found to fix itself rigidly to DNA and starts reeling in DNA from one side only, like a sailor on a boat reels in a hawser. Another interesting result: when the DNA is under tension, the looping process slows down. Apparently, with tension, condensin seems to struggle more to create a loop.
It is not pure academic interest, as it can also be important for medicine: almost all major diseases originate from defects on the molecular level within cells. Problems with the protein family to which condensin belongs, the SMC proteins, are related to hereditary conditions such as Cornelia de Lange Syndrome.
Condensin is also crucial in the organisation of the chromosomes during cell division, and errors in the process can result in cancer. A better understanding of these processes is vital for tracking down the molecular origins of serious illnesses.
Real-time imaging of DNA loop extrusion by condensin
Authors: Mahipal Ganji,1 Indra A. Shaltiel,2* Shveta Bisht,2* Eugene Kim,1 Ana Kalichava,1 Christian H. Haering,2† Cees Dekker1†
1 Department of Bionanoscience, Kavli Institute of Nanoscience Delft, Delft University of Technology, Delft, Netherlands.
2 Cell Biology and Biophysics Unit, Structural and Computational Biology Unit, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.
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Credit: Cees Dekker lab, Kavli Institute of Nanoscience, Delft University of Technology.
Page 1,4,6,9,11: Artwork from the 3 November 2017 cover of Science. Illustration: C. Bickel/Science; coordinates Cees Dekker/Delft University of Technology and Christian Haering/European Molecular Biology Laboratory. Used with permission from AAAS. Further distribution of this material is not permitted without prior permission from AAAS
Animation made by Scixel