Researchers discover DNA ‘repair’ enzyme that could enhance cancer treatments


Published July 30, 2013


Researchers have discovered an enzyme responsible for repairing single DNA strands damaged through cell division, which they hope will someday lead to better treatments for cancer, Parkinson’s and Alzheimer’s disease.

As we grow, the number of cells in our body must grow as well.  In order to multiply, a cell’s DNA must divide into two strands, creating two identical templates for the genomes of the “daughter” cells.

But every time cell division occurs, the cell’s genome is exposed, and this very important genetic material is left vulnerable to attacks from reactive oxygen species (ROS) – toxic molecules created through respiration.  If damaged by an ROS, the genetic information carried in a cell may change, and these genetic mutations can lead to disorders associated with DNA damage, such as cancer and neurodegenerative diseases.

Fortunately, the body has a natural way of repairing DNA harmed through the replication process, and researchers from the University of Texas Medical Branch in Galveston (UTMB), Texas have now figured out how the process works – a discovery that could lead to much more effective cancer treatments and maybe even the reversal of age-related diseases.

“We have so much damage (our cells are) continuously being exposed to, so we have to have a very efficient system of repair before that damage is replicated,” lead author Dr. Sankar Mitra, a professor in the department of biochemistry and molecular biology at UTMB, told  “If repair doesn’t occur first, replication is going to happen with the damaged genome.”

In a study published in the Proceedings of the National Academy of Sciences, Mitra and his team describe the work of an enzyme called NEIL1, a molecule that had been previously associated with the replication process.  In order to understand NEIL1’s mechanisms, the researchers suggest comparing DNA strand separation to the opening of a zipper.

As the zipper opens (or the strand divides), the DNA’s nucleobases are exposed, so that a group of proteins – known as the pre-replication complex – can bind to the single strands and copy them back into double strands.  The NEIL1 enzyme is part of this protein package.

However, it is during this copying process that the DNA’s bases are most susceptible to ROS damage.

“The most common genome damage is oxygen damage; it is the most chemical damage you’re exposed to,” Mitra said. “You cannot survive without oxygen, but because you’re breathing huge liters of oxygen every day, you’re continuously producing these particles – which in turn cause damage.”

According to Mitra, ROS damage occurs rather frequently throughout cell division and replication.  Fortunately, as soon as this damage occurs, NEIL1 recognizes the genetic change, and subsequently binds to the damaged site.  Once attached to the changed bases, it halts the replication process in its tracks.

“When they bind to that damage, the NEIL1 enzymes don’t allow replication to proceed,” Mitra explained. “When genome replication stops, the mechanism then is regression of the replication fork. So going backwards, like a zipper, the two strands come back together again.”

Once the strands have joined together, the NEIL1 – still bound to the damaged area – then fixes the genetic mutation before falling off the cell’s DNA.

Mitra and his team discovered NEIL1’s mechanisms through a series of in vitro experiments in their lab. They argue that knowing NEIL1’s function in the replication process could have huge implications for the future of cancer therapies.  For example, blocking or inhibiting the expression of NEIL1 in cancer cells could make them more susceptible to current cancer medications.

“All cancer drugs kill cells by targeting the DNA, because if the genome is damaged and if it’s not repairable, it causes the cancer cell to die.  But most of the time cancer comes back because some resistance occurs, and one mechanism of resistance is repair activity,” Mitra said. “But if you increase susceptibility of cancer cells to genome damage, then they’ll be much more sensitive to the drugs, and they can be killed more easily.”

Mitra also noted an even more incredible byproduct of his research: reversing the damage done by age-related diseases such as Parkinson’s and Alzheimer’s.  He said that boosting NEIL1 expression could potentially repair ROS-related genome damage in the elderly population.

“We don’t know how to increase the level of this enzyme, however there are ways to increase its expression,” Mitra said.  “Epigenetically, you can change the level of NEIL1 by changing a particular chromosomal function so that the level of this enzyme goes up.”

But most importantly, a better understanding of the cell replication repair process is crucial to the future of genetic research, according to Mitra.

“Genome damage repair is essential for survival of the human species, and we need to understand the mechanisms,” Mitra said. “If we have a comprehensive picture of how this damage repair occurs in various situations, then we can provide the window to developing new approaches to improving the process.”