Uncovering Repair Mechanisms to Fix DNA Double-Strand Breaks
“The opportunity of defeating the enemy is provided by the enemy himself,” pronounced Chinese military strategist and philosopher Sun Tzu. Scientists have long recognized that the enemy known as cancer has evolved a wide array of survival strategies over the millennia. By understanding those strategies, researchers at the Mays Cancer Center, home to UT Health San Antonio MD Anderson, are working to also uncover its weakness.
“There is a whole slew of things that can damage your DNA,” says Sandeep Burma, PhD, the Mays Family Foundation Distinguished Chair in Oncology at the Mays Cancer Center. “What we study is the most toxic and the most carcinogenic kind of damage which is the DNA double-strand break. This break causes genomic instability and precipitates tumor development.”
DNA is amazingly stable, but humans have so much of it there are bound to be occasional breaks. Most are simple, single-strand breaks easily repaired by the cellular machinery. The more dangerous double-strand breaks, ironically, can be caused by the powerful radiation commonly used to kill cancer cells in traditional cancer therapy. “That makes studying and understanding these DNA breaks doubly important because if they are not fixed properly by the cell, they may cause cancer while, at the same time, these breaks are induced by radiation to kill cancer cells,” said Dr. Burma, vice chair for research in the Department of Neurosurgery in the Joe R. and Teresa Lozano Long School of Medicine at UT Health San Antonio. In addition to breaks, our DNA is also subject to a plethora of other forms of DNA damage caused by the byproducts of normal cellular activity. While DNA repair researchers tend to study DNA double-strand breaks in isolation, in reality DNA breaks usually have other forms of DNA damage nearby resulting in so-called “complex DNA breaks.”
The results of the study to uncover the repair mechanisms that fix such complex DNA double-strand breaks were published in June in the journal Nature Communications. First author James Daley, PhD, research-track faculty in the Department of Biochemistry and Structural Biology at UT Health San Antonio, was joined by senior co-authors Dr. Burma; Patrick Sung, DPhil, the Robert A. Welch Distinguished Chair in Chemistry at UT Health, and Robert Hromas, MD, FACP, dean of the Long School of Medicine at UT Health.
Human cells typically use two different methods to repair DNA breaks. A simpler method is called non-homologous end joining wherein the broken DNA ends are quickly rejoined but with loss of some genetic information at the break site. The other method, called homologous recombination, is slower and complicated but is much more accurate and better able to preserve the genome. Homologous recombination begins with a critical process called “end resection” where one of the strands of DNA at a break is chewed back by multiple enzymes called resection nucleases. What was unclear, until this study, was why cells harbor multiple nucleases when they seemingly accomplish the same task. Dr. Daley’s research provided the answer to this conundrum.
“People tend to be very specialized in the field of DNA repair,” Dr. Burma says. “Double-strand break repair scientists look at double-strand breaks in isolation. But what really happens when you have a double-strand break is that there is very likely to be other forms of DNA damage nearby.” When a driver has a fender-bender in his car, it may take several different specialists to get it back on the road: a mechanic, a body repair specialist, and maybe an auto painter. Similarly, researchers found, for the first time, that the different enzymes involved in “end resection” are actually specialized to handle DNA breaks with different types of collateral DNA damage nearby.
“These findings have relevance to cancer therapy because if you find how these other forms of collateral damage around double-strand breaks influence the repair work, you can start to think about ways of making radiation more effective on tumors while less toxic to normal tissue,” Dr. Burma says.
An example of exploiting the weakness in a cancer cell’s ability to repair its own DNA is evident in BRCA1- and BRCA2-deficient breast tumors. The BRCA1 and BRCA2 genes are absolutely necessary for repair by homologous recombination. Without them, the cancer cells can still attempt repairs, but they now must use less efficient backup pathways, according to Dr. Sung, a leading expert in homologous recombination. “If one can find a way to shut down these backup pathways, then the tumor would be rendered extremely sensitive to DNA damaging cancer drugs. The more we study the individual steps of homologous recombination-mediated DNA repair, the more we come to appreciate the underlying complexity,” Dr. Sung notes.
Dr. Hromas said this research will have a direct impact on advancing cancer therapeutics. “All cancer arises because of at least one mistake in DNA repair,” he says. “About one-third of cancers start out as normal cells but develop a defect in one of the multiple DNA repair pathways and this defect then leads to the mutation-causing cancer.” Those cancer cells with a defective pathway become “addicted” to the other less efficient pathways to survive.
“By identifying the other repair pathways these cancers become addicted for survival, scientists can generate inhibitors to these essential pathways which would be lethal to the tumor. These would be new and effective treatments for these previously untreatable cancers,” Dr. Hromas said. Such drugs would not be toxic to normal cells since normal cells use the normal repair pathways which are unaffected.
Recent advances in new types of radiation therapy that are even more efficient at killing cancer cells make the research timely. Carbon-ion therapy, for example, uses isolated atoms of carbon traveling at almost the speed of light to destroy cancer cells. “Carbon ions are more effective at killing cancer cells,” Dr. Burma says, “as they can cause even more complex breaks. If we are able to pinpoint the resection enzymes critical for repairing such breaks, we could develop inhibitors to make Carbon-ion therapy even more effective.” The research was funded in part by a NASA grant to Dr. Burma as space travel leaves astronauts susceptible to complex double-strand breaks from cosmic radiation unfiltered by the earth’s protective atmosphere and magnetic fields. Other funding for the research included a team science grant from the Gray Foundation’s Basser Initiative, a Cancer Prevention & Research Institute of Texas Recruitment of Established Investigators Award, and grants from the National Cancer Institute.
Sometimes, scientific breakthroughs come from just asking the right questions like “Why does DNA end resection involve so many pathways?” That’s just part of the discovery process, explains Dr. Burma. “You can ask questions nobody has ever asked before and then try to answer them. Doing basic science in a clinical environment like UT Health is very satisfying since you can take new findings, translate them to the clinic, go through the trials, and complete the entire translational process. All of that is possible at UT Health and the Mays Cancer Center.”
The work of understanding the DNA repair and damage response system continues as more than 1,000 genes are likely involved in the intricate process. But in that understanding lies the opportunity to defeat the enemy.