Electrons use DNA like a wire for signaling DNA replication

February 24, 2017 by Whitney Clavin, California Institute of Technology
Electrons use DNA like a wire for signaling DNA replication
A protein called DNA primase (tan) begins to replicate DNA when an iron-sulfur cluster within it is oxidized, or loses an electron (blue and purple). Once this primase has made an RNA primer, a protein signaling partner, presumably DNA polymerase alpha (blue), sends an electron from its reduced cluster, which has an extra electron (yellow and red). The electron travels through the DNA/RNA helix to primase, which comes off the DNA. This electron transfer signals the next steps in replication. Credit: Caltech

In the early 1990s, Jacqueline Barton, the John G. Kirkwood and Arthur A. Noyes Professor of Chemistry at Caltech, discovered an unexpected property of DNA—that it can act like an electrical wire to transfer electrons quickly across long distances. Later, she and her colleagues showed that cells take advantage of this trait to help locate and repair potentially harmful mutations to DNA.

Now, Barton's lab has shown that this wire-like property of DNA is also involved in a different critical cellular function: replicating DNA. When cells divide and replicate themselves in our bodies—for example in the brain, heart, bone marrow, and fingernails—the double-stranded helix of DNA is copied. DNA also copies itself in reproductive cells that are passed on to progeny.

The new Caltech-led study, based on work by graduate student Elizabeth O'Brien in collaboration with Walter Chazin's group at Vanderbilt University, shows that a key protein required for replicating DNA depends on electrons traveling through DNA.

"Nature is the best chemist and knows exactly how to take advantage of DNA chemistry," says Barton, who is also the Norman Davidson Leadership Chair of Caltech's Division of Chemistry and Chemical Engineering.

"The electron transfer process in DNA occurs very quickly," says O'Brien, lead author of the study, appearing in the February 24 issue of Science. "It makes sense that the cell would utilize this quick-acting pathway to regulate DNA replication, which necessarily is a very rapid process."

The researchers found their first clue that DNA replication might involve the transport of electrons through the by taking a closer look at the proteins involved. Two of the main players in DNA replication, critical at the start of the process, are the proteins DNA primase and DNA polymerase alpha. DNA primase typically binds to single-stranded, uncoiled DNA to begin the replication process. It creates a "primer" made of RNA to help DNA polymerase alpha start its job of copying the single strand of DNA to create a new segment of double-helical DNA.

DNA primase and DNA polymerase alpha molecules both contain iron-sulfur clusters. Barton and her colleagues previously discovered that these metal clusters are crucial for DNA electron transport in DNA repair. In DNA repair, specific proteins send electrons down the double helix to other DNA-bound repair proteins as a way to "test the line," so to speak, and make sure there are no mutations in the DNA. If there are mutations, the line is essentially broken, alerting the cell that mutations are in need of repair. The iron-sulfur clusters in the DNA repair proteins are responsible for donating and accepting traveling electrons.

Barton and her group wanted to know if the iron-sulfur clusters were doing something similar in the DNA-replication proteins.

"We knew the iron-sulfur clusters must be doing something in the DNA-replication proteins, otherwise why would they be there? Iron can damage the DNA, so nature would not have wanted the iron there were it not for a good reason," says Barton.

Through a series of tests in which mutations were introduced into the DNA primase protein, the researchers showed that this protein needs to be in an oxidized state—which means it has lost electrons—to bind tightly to DNA and participate in DNA electron transport. When the protein is reduced—meaning it has gained electrons—it does not bind tightly to DNA.

"The electronic state of the iron-sulfur cluster in DNA primase acts like an on/off switch to initiate DNA replication," says O'Brien.

What's more, the researchers demonstrated that electron transport through DNA plays a role in signaling DNA primase to leave the DNA strand. (Though DNA primase must bind to single-stranded DNA to kick off replication, the process cannot begin in earnest until the protein pops back off the strand).

The scientists propose that the DNA polymerase alpha protein, which sits on the double helix strand, sends electrons down the strand to DNA primase. DNA primase accepts the electrons, becomes reduced, and lets go of the DNA. This donation and acceptance of electrons is done with the help of the iron-sulfur clusters.

"You have to get the DNA primase off the DNA quickly—that really starts the whole replication process," says Barton. "It's a hand off of electrons from one cluster to the other through the DNA double helix."

Many proteins involved in DNA reactions also contain iron-sulfur clusters and may also play roles in DNA electron transport chemistry, Barton says. What began as a fundamental question 25 years ago about whether DNA could support migration of continues to lead to new questions about the chemical workings of cells. "That's the wonder of basic research," she says. "You start with one question and the answer leads you to new questions and new areas."

Explore further: Structure of key DNA replication protein solved

More information: Elizabeth O'Brien et al. The [4Fe4S] cluster of human DNA primase functions as a redox switch using DNA charge transport, Science (2017). DOI: 10.1126/science.aag1789

Related Stories

Structure of key DNA replication protein solved

October 25, 2016

A research team led by scientists at the Icahn School of Medicine at Mount Sinai (ISMMS) has solved the three-dimensional structure of a key protein that helps damaged cellular DNA repair itself. Investigators say that knowing ...

Hijacking the double helix for replication

December 13, 2016

For years, scientists have puzzled over what prompts the intertwined double-helix DNA to open its two strands and then start replication. Knowing this could be the key to understanding how organisms - from healthy cells to ...

Protein complex prevents genome instability

January 19, 2017

An international collaboration between Osaka University and the Friedrich Miescher Institute for Biomedical Research (FMI) in Switzerland is investigating the repair process of a serious form of DNA damage that can lead to ...

Oxygen 'sensor' may shut down DNA transcription

June 19, 2012

(Phys.org) -- A key component found in an ancient anaerobic microorganism may serve as a sensor to detect potentially fatal oxygen, a University of Arkansas researcher and his colleagues have found. This helps researchers ...

Recommended for you

New targets in the battle against antibiotic resistance

November 16, 2018

Bacteria are increasingly resistant to available antibiotics. A team of chemists from the Technical University of Munich (TUM) have now identified important enzymes in the metabolism of staphylococci. Blocking these enzymes ...

AI heralds new frontiers for predicting enzyme activity

November 16, 2018

Researchers from the Departments of Chemistry and Engineering Science at the University of Oxford have found a general way of predicting enzyme activity. Enzymes are the protein catalysts that perform most of the key functions ...

2 comments

Adjust slider to filter visible comments by rank

Display comments: newest first

thingumbobesquire
not rated yet Feb 25, 2017
Bravo! Truly remarkable research that elucidates the unique chemistry of life.
BENRAS
not rated yet Feb 26, 2017
Congratulations to all who participated in this investigation. Might this suggest interrogation at the level of quantum interaction so as to further characterize same.

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.