“Cowcatcher” Enzyme Catching Medical Attention

By: Ansel Oommen, BS Toxicology Candidate c/o 2014

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DNA damage is the driving force behind aging, and, on a more serious note, the development of cancers.¹ While the stresses of life can be taxing on cells, the human body possesses a remarkable repair mechanism to remedy them. Researchers from the University of Texas Medical Branch have now discovered how that mechanism, which involves an enzyme called NEIL1, may prove to be useful in the fight against cancer and other age-related disorders such as Alzheimer’s and Parkinson’s disease.²

In the findings published in the Proceedings of the National Academy of Sciences, the researchers aptly describe the enzyme as a “cowcatcher” after an old device fixed to the front of locomotives.³ Similar to this device, which works by clearing the track of obstructions like cows, the enzyme searches for genetic errors and clears them.

The lead author Dr. Sankar Mitra explains, “basically the replication train is coming and the cowcatcher is in front to see if any damage is present. If it finds such damage, the train moves backward, you repair it, and the train starts moving forward again.” ³ The process of cell replication is risky yet essential to most biological processes. When DNA replicates, its stable double helix structure is unwound by a collection of proteins called the “pre-replication complex.” Two of the components of this complex are NEIL1 and its closely related cohort, NEIL2. The complex splits the DNA into two strands to be used as templates in the formation of the new DNA for the daughter cells.

The necessary separation of DNA strands exposes the body’s genetic blueprint, rendering it vulnerable to toxic insults from reactive oxygen species (ROS), which are natural byproducts of respiration. Each attack on the genome by the ROS can lead to mutations, and over time, these uncorrected mutations can manifest in a clinical disorder such as cancer. The free radicals modify the four bases that make up DNA to produce base lesions. This can prevent the DNA from triggering a stop to replication, which may make the cells immortal. The newly discovered NEIL1, at the forefront of the pre-replication complex, locates these lesions and binds to them on the DNA to signal a halt to replication.^2,3 By doing so, the two strands are realigned, allowing for repairs to be made. Afterwards, NEIL1 simply detaches from the DNA. And in the event that NEIL1 is unavailable, NEIL2 serves a similar function.⁴

There are promising clinical ramifications to the discovery of this enzymatic activity. Suppressing the expression of NEIL1 can make it more difficult for cancer cells to defy standard therapies. Without the ability to repair their genomes, the rapidly dividing cancerous cells become much more vulnerable to the genotoxic effects of ionizing radiation and antineoplastics. This can be especially important in preventing relapses that occur when cancer cells become resistant to therapy. Conversely, boosting the expression of the enzyme can help combat ROS induced damages commonly seen in the geriatric population, particularly in those who suffer from neurodegenerative diseases.

It is not surprising that the “cowcatcher” has garnered attention from both the media and the medical community. However, more research is needed to realize the full potential of this discovery.  For now, Mitra says “we don’t know how to increase the level of this enzyme; however, there are ways to increase its expression.”²With that hope, the researchers continue to explore cellular genome repair processes to further unlock the mystery behind cancer.

SOURCES:

1. “Biology of Aging: What Happens When DNA Becomes Damaged?” National Institute on Aging. http://www.nia.nih.gov/health/publication/genetics-aging-our-genes/what-happens-when-dna-becomes-damaged. Updated January 19, 2012. Accessed September 19, 2013.
2. Grush L. “Researchers Discover DNA ‘Repair’ Enzyme That Could Enhance Cancer Treatments.” Fox News. http://www.foxnews.com/health/2013/07/30/researchers-discover-dna-repair-enzyme-that-could-enhance-cancer-treatments/. July 30, 2013. Accessed September 21, 2013.
3. “‘Cowcatcher’ Enzyme Fixes Single Stranded DNA.” ScienceDaily. http://www.sciencedaily.com/releases/2013/07/130729161751.htm. Accessed September 21, 2013.
4. Hedge ML, Hedge PM, Bellot LJ, et al. “Prereplicative repair of oxidized bases in the human genome is mediated by NEIL1 DNA glycosylase together with replication proteins.” Proceedings of the National Academy of Sciences. 2013;110(33). http://www.pnas.org/content/early/2013/07/26/1304231110.full.pdf. July 26, 2013. Accessed September 21, 2013.