TAMPA, Fla. – Deoxyribonucleic acid (DNA), is the macromolecule that holds all hereditary and genetic information. Continuously under assault, alterations and damage to DNA can lead to many different health issues, including cancer. DNA is highly regulated within cells, where multiple mechanisms are at play to repair and protect its integrity. Scientists are still investigating these mechanisms to fully comprehend how these DNA repair processes are managed. Moffitt Cancer Center researchers recently identified a new mechanism that controls DNA repair. Their findings were published in the journal Cell Death & Differentiation.
DNA receives insults and is damaged by many different types of sources, including ionizing radiation (IR), oxygen radicals as well as errors made during the DNA replication process. “Mammalian cells are continuously bombarded by DNA damaging insults which threaten cell viability and genomic integrity,” explained Patsy McDonald, Ph.D., associate member in the Department of Cancer Physiology at Moffitt. These types of insults can cause replication fork collapse and double-stranded breaks within the DNA that can lead to cell death, or genetic alterations that may result in tumor development. Fortunately, cells have evolved multiple highly coordinated mechanisms to repair DNA damage to ensure continued growth, replication and cell survival. Alternatively, other mechanisms come into play to eliminate cells with too much damage.
Previously Moffitt researchers in the lab of Derek Duckett, Ph.D., senior member and Chair of the Department of Drug Discovery at Moffitt, collaborated with Duke University to demonstrate that chronic stress-induced β2-adrenergic–βarrestin-1 signaling pathway provokes genomic alterations by promoting the degradation of the protein p53. In the current study, the researchers performed experiments to determine if the protein βarrestin1 (βarr1) plays any additional role in the repair of DNA damage. They discovered that βarr1 interacts with the protein 53BP1 via a multiprotein complex. 53BP1 is known to be involved in the repair of double-stranded DNA breaks. The interaction between the two proteins causes 53BP1 to be targeted for protein degradation, thereby reducing its ability to repair DNA. Importantly, the researchers showed that mice lacking βarr1 survived longer following IR treatment than normal control mice. This demonstrates that loss of βarr1 expression is associated with resistance to the toxic effects of radiation treatment.
“These studies suggest that pharmacological blockade of the βarr1–53BP1 signaling cascade provides a novel strategy for developing therapeutic agents with radiation protection properties through enhanced repair of IR-induced DNA double-stranded breaks,” explained Duckett.
There are currently several drugs in development that may offer protection against IR; however, these agents target factors other than the DNA breaks themselves. “We anticipate that pharmacologically mimicking the βarr1 knockout phenotype would act as an effective countermeasure to IR and may also augment the efficacy of the current molecules under investigation,” said McDonald.
The study was supported by funds from the State of Florida to The Scripps Research Institute and institutional funds provided by Moffitt Cancer Center.
About Moffitt Cancer Center Moffitt is dedicated to one lifesaving mission: to contribute to the prevention and cure of cancer. The Tampa-based facility is one of only 51 National Cancer Institute-designated Comprehensive Cancer Centers, a distinction that recognizes Moffitt’s scientific excellence, multidisciplinary research, and robust training and education. Moffitt is a Top 10 cancer hospital and has been nationally ranked by U.S. News & World Report since 1999. Moffitt devotes more than 2 million square feet to research and patient care. Moffitt’s expert nursing staff is recognized by the American Nurses Credentialing Center with Magnet® status, its highest distinction. With more than 6,000 team members, Moffitt has an economic impact in the state of $2.5 billion. For more information, call 1-888-MOFFITT (1-888-663-3488), visit MOFFITT.org, and follow the momentum on Facebook, Twitter and YouTube.
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