The secrets of DNA looping could give us the upper hand in the fight against cancer

How does a cell package its jumble of genetic data into neat chromosomes for division? The DNA in our cells, after all, extends to around two meters in length, and needs to fit into a nucleus around 1/50th the size of a grain of salt. How on earth does it arrange that tangle before splitting into two?

New research has thrown a literal light on the process, filming a protein complex called condensin as it draws loops from DNA.

Previous studies have theorised that condensin acts like a tiny motor to create loops in DNA; the idea being that many of these folds allow a cell to compact its genome for distribution between daughter cells. Up to now, however, this role has not been proven. By isolating a DNA molecule and carefully orientating it with a condensin complex beneath a microscope, scientists from the Kavli Institute of Delft University and EMBL Heidelber have filmed the protein in action.

“The technique may appear very straightforward (‘Just image the DNA and the condensin’) but it is far from trivial,” professor Cees Dekker, head of the research group at the department of bionanoscience in Delft, tells Alphr. “One needs to image the DNA without too much photo damage.

“When you shine light on DNA to make it visible, that light can also create damage (called photodamage), and therefore break the DNA. This happened, for example, when we started this research eight years ago with more standard colour dye that would nick and break the DNA within seconds.”

Mahipal Ganji, a postdoc in Cees Dekker group of at Delft, explains that the first step in the new imaging process was to fix two end of a DNA molecule onto a surface and carefully apply colour dye: “By then applying a flow in the fluid perpendicular to the molecule, we oriented the DNA in a U-shape and brought it into the focal plane of our microscope. Amazingly, we could then see a single condensin bind and start extruding a loop.”

According to Dekker, the footage “settles the debate” about condensin’s ability to form loops in DNA. The team also observed that the reeling is asymmetric, with condensin only pulling DNA from one side of its anchored point. The process of looping only takes a modest amount of ATP to fuel the condensin, suggesting the protein complex doesn’t pull the DNA base by base, but in large chunks. The tiny motor does this remarkably fast, reeling up to 1,500 base pairs per second.

The findings have the scope to not only elucidate a fundamental mechanism of mitosis and meiosis, but can be used to help cure medical problems associated with the family of proteins condensin is part of, known as SMC proteins. As Dekker explains, this could help us better understand how to fight cancer:

“The SMC proteins are crucial for the organisation of chromosomes. Disruption of the correct distribution of chromosomal material to daughter cells is associated with cancer. The basic understanding of the SMC proteins thus lies at the heart of understanding the disruptive processes that lead to cancer. More specifically, mutations in the SMC proteins are related to hereditary conditions such as Cornelia de Lange Syndrome.”

The findings from the Kavli Institute of Delft University and EMBL Heidelber are published today in the journal Science.

Image credit: Cees Dekker Lab TU Delft/Scixel

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