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A New Study Solves One of the Largest DNA Replication Mysteries

Replication is the biggest natural magic trick. Look carefully, and before your eyes, you will see a single cell blurring into almost identical copies. Presto.

After more than half a century of research on molecular genetics, it will be easy to assume that we already know this biological magic – but that is not the case.

Now, by applying cutting-edge technology, researchers have revealed important details that show how DNA replicates itself.

"It's quite a mystery," said molecular biologist David Gilbert of Florida State University.

"Replication seems resilient to everything we try to disturb it. We have explained it in detail, showing it changes in different cell types and that it is disrupted by disease.

"But until now, we can't find the last part, the control element or the DNA sequence that controls it."

Open any textbook on this topic and you will find a diagram showing how long deoxyribonucleic acid (DNA) filaments act like the longest jigsaw puzzle in the world, building strands that are almost identical through the use of intelligent chemistry and a number of diligent proteins.

Most of us have the luxury of delving into the details of this enzymatic magic in recognition of the overall trick.

But for researchers, the complexity of this process – especially in organisms like our mammals – has proven difficult to decompose.

Like all good magic tricks, timing is very important. But confusing the regulatory protein does not seem to make much difference to this as expected, showing the rhythm right behind replication is more related to the DNA molecule acting on itself.

To uncover the chemical architecture that governs DNA replication, Gilbert and his team turned to the emerging technology known as CRISPR to cut mouse chromosomes to find out which factors make a difference.

CRISPR is a molecular tool based on the process used by bacteria to identify threatening viral genes. Once certain genetic codes are found, enzymes associated with CRISPR can hone and break down sequences, effectively eliminating threats.

In the hands of researchers, this same system can be used to cut designated DNA sequences.

Gilbert uses it to target various structures in the DNA architecture of mouse embryonic stem cells, switch around or cut them completely.

The initial focus is on the binding site for a protein called CCCTC-binding factor (CTCF). This protein helps regulate the entire transcription process, making the landing zone a natural place to find locations that regulate more spatiotemporal DNA operations.

But this fiddling doesn't have much effect on the actual time of the replication process. Something else must be working.

Finding this virtual needle in a haystack will require more than a little luck.

It comes in the form of high resolution 3D analysis of contact sites made by DNA itself. In what is slightly similar to the close up of the hands of a skilled wizard at work, the team can find & # 39; fingertips & # 39; in action.

In particular, they identified several key locations outside the boundaries of the CTFC. Destroying them causes chaos – when replication is thrown, the DNA architecture itself is weakened, and transcription is answered.

"Removing these elements shifts the replication time of the segment from the beginning to the end of the process," Gilbert said.

"This is one moment where only one result knocks your socks."

The results pave the way for new research on health and pathology. By pinpointing the mechanism responsible for DNA replication time, researchers might find a process that causes certain diseases.

"If you multiply at different times and places, you might arrange a completely different structure," Gilbert said.

We have traveled a long way since physicist Erwin Schrödinger made predictions about & # 39; aperiodic crystals & # 39; which can explain cell replication uses a little more than basic chemical physics.

More than seven decades later, the physics behind molecular genetics is still reluctant to share its secrets.

Not that it makes the biggest natural magic show no less amazing.

This research was published on Cell.

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