Surfing DNA

Enzyme catches a ride to fight infection

Scientists have shown for the first time that an enzyme crucial to keeping our immune system healthy “surfs” along the strands of DNA inside our cells. The researchers used extremely powerful microscopy to watch how the enzyme AID (activation-induced deoxycytidine deaminase) moves around and interacts with other molecules.

The enzyme ‘AID’ uses a biological motor to surf along DNA strands.
The enzyme ‘AID’ uses a biological motor to surf along DNA strands.
Source: pixabay

They were able to see that it catches a free ride on top of another enzyme, which has its own motor. “Before now, no one has shown that an enzyme can ride on top of a motor-enzyme,” says David Rueda who leads the Single Molecule Imaging group at the MRC Clinical Sciences Centre at Imperial College, and who led the team whose research is published today in Nature Communications.

AID helps our immune system to recognise and respond to pathogens such as bacteria and viruses. Each strain of pathogen has a unique pattern of molecules on its surface. These molecules come in all shapes and sizes, so that the immune system can distinguish between different pathogens.

Small proteins called antibodies bind to these molecules. Once bound, the antibodies act as a guide for the immune system by flagging up pathogens for destruction. But each antibody binds only to one particular shape. To respond to new pathogens, our bodies must constantly make new antibodies with new shapes. This is where AID comes in.

When immune cells produce antibodies, they must first make a copy of the gene, or section of DNA, that contains information about how to make an antibody. AID makes subtle changes, or mutations, to this section of DNA in random places. Some of these random mutations will result in the production of antibodies that “fit” the shapes of pathogens.

To mutate the DNA, scientists knew that AID must first move into position on the strand but they didn’t know how this happened. Rueda’s team is the first to observe its movements in real time.

The new findings show that AID is drawn towards the DNA strand when antibody production begins. In this initial step the DNA is copied by an enzyme, called a polymerase, which draws power from its motor to move along the strand.

As the polymerase moves, it makes a bubble and AID surfs this bubble much like a surfer rides a wave. They move together, and during this time AID makes random mutations in the DNA. Eventually, AID makes polymerase stall and, like a surfer on a wave that has reached the shore, AID and the polymerase come to a halt and fall off or move away from the strand.

“What’s interesting is that the polymerase has a motor that allows it to move in one direction but AID doesn’t, so AID takes advantage of the polymerase motor to follow it,” says Rueda. “We don’t know all the molecular details of the mechanism yet, but we’ve shown that AID follows the polymerase, and that this is how it goes from one side of the DNA to another.”

The microscopy technique used by the team is called single-molecule fluorescence resonance energy transfer, or smFRET. This allowed them to see exactly what the AID molecule was doing at any given moment. Although smFRET was developed almost two decades ago, the team is the first to use it to explore how AID manoeuvres itself into position on a strand of DNA.

On occasion, AID mutates the DNA in the wrong place or at the wrong time, and this can contribute to the development of a range of cancers, including breast, colon and lung cancer. According to Rueda, if scientists can find out more about AID and what happens when it goes wrong, they may be able to develop approaches to control its action, and this may one day help to develop new treatments for these types of cancer.


Source: MRC Clinical Sciences Centre

04.01.2016

Read all latest stories

Related articles

Photo

State-of-the-art

First pictures of cells' DNA-copying machinery

The first-ever images of the protein complex that unwinds, splits, and copies double-stranded DNA reveal something rather different from the standard textbook view. The electron microscope images,…

Photo

Between man and molecule

The hunt for genetic risk factors

Professor Christoph M Friedrich researches the interface between man and molecule. Born in Westphalia, Germany, the professor for biomedical computer science at Dortmund University of Applied…

Photo

It's all connected

Understanding the "wiring diagrams" of genes in complex tissues

How is the activity of all genes in cells of higher organisms interconnected? And how are the genetic "wiring diagrams" of the cells in complex tissues coordinated with each other?…

Related products

Agena Bioscience - MassARRAY Colon Panel

Amplification/Detection

Agena Bioscience - MassARRAY Colon Panel

Agena Bioscience GmbH
Eppendorf – BioSpectrometer fluroescence

Research Use Only (RUO)

Eppendorf – BioSpectrometer fluroescence

Eppendorf AG
Eppendorf – Mastercycler nexus X2

Research Use Only (RUO)

Eppendorf – Mastercycler nexus X2

Eppendorf AG
Eppendorf – μCuvette G1.0

Research Use Only (RUO)

Eppendorf – μCuvette G1.0

Eppendorf AG
Orion Diagnostica Oy – Orion GenRead

Amplification

Orion Diagnostica Oy – Orion GenRead

Orion Diagnostics Oy