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Armed Forces in the Cell Keep DNA Healthy

David Coppedge
Photo credit: U.S. Army, Public domain, via Wikimedia Commons.

Science reporters struggle for metaphors to describe the complex operations they see going on in the cell. For example:

The Orchestra

News from the University of Geneva likens the human genome to a “complex orchestra.” Their research led to “unexpected” and “surprising” findings showing “harmonized and synergistic behavior” in the regulation of genes. The metaphor of a conductor keeping all the various players in harmony came to mind:

A team of Swiss geneticists from the University of Geneva (UNIGE), the École Polytechnique Fédérale de Lausanne (EPFL), and the University of Lausanne (UNIL) discovered that genetic variation has the potential to affect the state of the genome at many, seemingly separated, positions and thus modulate gene activity, much like a conductor directing the performers of a musical ensemble to play in harmony. These unexpected results, published in Cell, reveal the versatility of genome regulation and offer insights into the way it is orchestrated. [Emphasis added.]

The Armed Forces

Another metaphor popular among reporters is “armed forces.” This metaphor will prove instructive as we read about DNA protection and damage repair. Let’s look at some of the stages in this process where we will find soldiers, emergency medical technicians, ambulances and military hospitals in action, each well trained and equipped for defense.

Surveillance and Inspection

Any disciplined military operation requires high standards. Soldiers at boot camp know that drill sergeants can be ruthless when inspecting rifles, shoe shines, and barrack beds. Similarly, machines in the genome inspect DNA for errors and won’t tolerate less than perfection. A news item from North Carolina State University describes MutS, a machine that inspects unzipped DNA strands looking for errors. Any mismatch makes this drill sergeant stop and stare the recruit in the face, even if he is one in a million.

Fortunately, our bodies have a system for detecting and repairing these mismatches — a pair of proteins known as MutS and MutL. MutS slides along the newly created side of the DNA strand after it’s replicated, proofreading it. When it finds a mismatch, it locks into place at the site of the error and recruits MutL to come and join it. MutL puts a nick in the newly synthesized DNA strand to mark it as defective and signals a different protein to gobble up the portion of the DNA containing the error. Then the nucleotide matching starts over, filling the gap again. The entire process reduces replication errors around a thousand fold, serving as our body’s best defense against genetic mutations and the problems that can arise from them, like cancer.

First Response

If casualties occur, they have to be detected. A protein named ATF3 is captain of a squad that acts as “first responder” to DNA damage, as this from Georgia Regents University explains. Let’s say a DNA strand breaks because of sunlight, chemotherapy or a cosmic ray. If not corrected quickly, the cell could become cancerous or die. What happens first?

In the rapid, complex scenario that enables a cell to repair DNA damage or die, ATF3, or activating transcription factor 3, appears to be a true first responder, increasing its levels then finding and binding to another protein, Tip60, which will ultimately help attract a swarm of other proteins to the damage site.

Combat Operations

Viruses have invaded! The armed forces go into high alert. The Salk Institute for Biological Studies describes the flurry of activities that result, because every organism “must protect its DNA at all costs.” 

Before panicking, the cell’s commanding officers need intelligence. If a DNA break puts the cell in stress, was it a natural break, let’s say from a cosmic ray, or from a virus, like an insurgent tossing a grenade? A false move could lead to friendly-fire casualties. 

The researchers explain how the cell figures out if the DNA damage was internal or external. First, the MRN complex gives the “all hands on deck” signal. It stops replication and other cell operations until the break is mended. 

What’s interesting is that even a single break transmits a global signal through the cell, halting cell division and growth,” says O’Shea. “This response prevents replication so the cell doesn’t pass on a break.”

The viral response begins the same way, but doesn’t give the global alarm. Instead, the alarm is localized, and sentries in the area dispatch the invaders. There’s a reason for this. “If every incoming virus spurred a similarly strong response, points out O’Shea, our cells would be frequently paused, hampering our growth.” But when the cell becomes preoccupied with DNA damage repair, the viruses can infiltrate.

A video in the article applies the armed forces metaphor:

Govind Shah: “DNA repair proteins serve as security guards inside the nucleus. They catch virus DNA and escort them out of the cell. If a cell experiences a huge amount of DNA damage, then these security guards will be pulled away from the viral DNA and allow the viral DNA to replicate to high levels.”

Clodagh O’Shea: “We discovered that if you have DNA damage in your own genome, and the alarm goes off, actually that recruits in all of the forces: all of the police, national guard–everyone’s there. All the forces are dealing with your own DNA damage, and there’s nothing left to actually even see or actually turn off the virus.”

This gave them an idea. Shah says, “So why not use this to kill cancer cells” with viruses engineered to enter tumor cells? The programmed response they discovered will cause the cell to let the viruses in while it’s preoccupied with fixing DNA breaks. “If the cell can’t fix the DNA break, it will induce cell death-a self-destruct mechanism that helps to prevent mutated cells from replicating (and thus prevents tumor growth).” 


We’re all familiar with the images of battlefield helicopters delivering medics to give first aid to the wounded, or airlifting them to the nearest triage station or hospital. The cell nucleus has hospitals, an article at Biotechniques says, and “A molecular ambulance for DNA” knows how to get the casualties to the emergency room.

Double-strand breaks in DNA are a source of stress and sometimes death for cells. But the breaks can be fixed if they find their way to repair sites within the cell. In yeast, one of the main repair sites resides on the nuclear envelope where a set of proteins, including nuclear pore subcomplex Nup84, serves as a molecular hospital of sorts. The kinesin-14 motor protein complex, a “DNA ambulance,” moves the breaks to repair sites, according to a new study in Nature Communications.

Researchers at the University of Toronto found it “very surprising” that the ambulance driver is the well-known motor protein kinesin-14 (see our animation of kinesin at work below). 

Hospital Staff

News from the University of Texas MD Anderson Cancer Center introduces some of the specialists in the DNA repair hospital: fumarase, a metabolic enzyme; DNA-PK, a protein kinase; and histone methylation enzymes that regulate the repair process. These skilled doctors perform restorative surgery for “DNA double-strand breaks (DSBs),” which “are the worst possible form of genetic malfunction that can cause cancer and resistance to therapy.”

Clean-Up Crew

Cells invest a lot of energy in their ribosomes, the organelles that translate DNA. Ribosomes are assembled from protein and RNA domains. What happens with the leftovers? An item from the University of Heidelberg describes molecular machines that barcode the fragments for delivery to a barrel-shaped shredder called the exosome. Though not described in military terms, the agents are under strict orders and required to pass through checkpoints.

According to Prof. Hurt, the production of ribosomes is an extremely complex processthat follows a strict blueprint with numerous quality-control checkpoints. The protein factories are made of numerous ribosomal proteins (r-proteins) and ribosomal ribonucleic acid (rRNA). More than 200 helper proteins, known as ribosome biogenesis factors, are needed in the eukaryotic cells to correctly assemble the r-proteins and the different rRNAs. Three of the total of four different rRNAs are manufactured from a large precursor RNA. They need to be “trimmed” at specific points during the manufacturing process, and the superfluous pieces are discarded. “Because these processes are irreversible, a special check is needed,” explains Ed Hurt.

The number of “armed forces” personnel involved in DNA defense and cell quality control is astonishing. It’s beyond a well-conducted orchestra. It’s like a military operation, with strict protocols, hierarchical command structure and trained specialists. These systems are goal-oriented: they exist to protect the genome. They are on duty inspecting components even when nothing is wrong. And when things do go wrong, they know just what to do, as if well-trained in following orders.

We aren’t surprised to notice that these articles say nothing about evolution. Why? Because we all know from our experience that phenomena characterized by hierarchical command and control systems with documented procedures and skilled agents are always intelligently designed.

This article was originally published in 2015.