Zigzag DNA

DNA in a cell can normally be compared to spaghetti on one's plate: a large tangle of
strands. To be able to divide DNA neatly between the two daughter cells during cell division,
the cell organises this tangle into tightly packed chromosomes. A protein complex
called condensin has been known to play a key role in this process, but biologists had no
idea exactly how this worked. Until February 2018, when scientists from the Kavli Institute
at Delft University of Technology, together with colleagues from EMBL Heidelberg, showed
in real time how a condensin protein extrudes a loop in the DNA. Now, follow-up research
by the same research groups shows that this is by no means the only way condensin
packs up DNA. The researchers discovered an entirely new loop structure, which they call
the 'Z loop'. They publish this new phenomenon on 4 March in Nature, where they show,
for the first time, how condensins mutually interact to fold DNA into a zigzag structure.

More than just loops

'It started with the question of whether DNA
can be folded into a compact chromosome
by means of single loops, or whether there
is more to it,' says TU Delft postdoctoral
Dr. Eugene Kim. 'We wanted to see several
condensins at the same time. During the
experiments, we discovered an interesting
new form of folded DNA, which clearly differs
from a single loop, and which surprisingly also
occurs much more often than those loops.
We were able to figure out experimentally that
DNA is folded in a kind of zigzag structure.
We named these structures Z-loops, since
the DNA is folded in the form of the letter Z.'
The researchers mainly examined the
structure out of curiosity. 'It wasn't predicted
at all,' says Kim. We wondered: how is such
a structure made by two condensins, what is
the underlying molecular mechanism?

Zigzag structure through collaboration

Research leader Prof. Cees Dekker explains:
'The creation of a Z-shaped structure begins
when one condensin lands on DNA and makes
a single loop. Then, a second condensin
binds within that loop and starts to make its
own loop, creating a loop in a loop. When the
two condensins meet during their tug-of-war,
something surprising happens: the second
condensin hops over the first one and grabs
the DNA outside the loop, continuing its way
along the DNA. We were very surprised that
condensin complexes can pass each other.
This is completely at odds with current models,
which assume that condensins block each
other when they meet.'

Seeing the condensins at work

In cells, DNA is such a complex tangle that it
is very difficult to isolate and study the loop
extrusion process. The researchers therefore
visualized the loop formation in 1 DNA molecule
on a glass plate. They attached the two
ends of the DNA molecule to a surface and
stuck fluorescent labels to the DNA and the
condensin proteins. By then applying a flow in
the liquid, perpendicular to the molecule, the
researchers were able to make the DNA take
on a U-shaped form and bring it under the
microscope for imaging.

Medical relevance

This research is an important step in the
fundamental understanding of DNA in our
cells. It also has medical relevance. Problems
with the protein family to which condensin
belongs, the SMC proteins, are related to
hereditary disorders, such as Cornelia de
Lange Syndrome. Condensin is also crucial in
the organisation of chromosomes during cell
division; errors in this process can lead to cancer.
A better understanding of the underlying
molecular mechanisms is vital in the search
for the molecular origin of serious diseases.