Deoxyribonucleic acid (DNA) - is a macromolecule that contains all hereditary and genetic information. Constantly subjected to attacks, changes and DNA damage can lead to a variety of different health problems, including cancer. DNA is tightly regulated in cells where there are numerous mechanisms for restoring and protecting its integrity. Scientists are still investigating these mechanisms in order to fully understand how these DNA repair processes are controlled. Researchers at Moffitt Cancer Center recently identified a new mechanism that controls DNA repair. Their results were published in Cell Death & Differentiation journal.

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DNA damage is incurred in many different types of sources including ionizing radiation (IR), oxygen radicals, as well as errors in DNA replication. "Mammalian cells are constantly bombarded with DNA damage, which threaten the viability of the cells and genome integrity", - explains Patsy MacDonald, Ph.D., an associate member of the cancer physiology department at Moffitt. These types of injuries can cause the collapse of replication forks and double-strand breaks in DNA, which can lead to cell death and genetic changes that may lead to tumor development. Fortunately, cells have developed many highly coordinated mechanisms for repair of DNA damage in order to ensure continued growth, replication and survival of cells. Alternatively, other mechanisms come into play to eliminate cells with too much damage.

Earlier, Moffitt researchers in the laboratory of Derek Duckett, PhD, Senior Fellow and Head of the Department of drug discovery at Moffitt, collaborated with Duke University, to demonstrate that induced by chronic stress pathway signaling .beta.2-adrenergic, beta-arrestin-1 triggers genomic changes, contributing to degradation of p53 protein. In the current study, the researchers conducted experiments to determine whether the protein plays βarrestin1 (βarr1) any further role in the recovery of DNA damage. They found that the protein interacts with βarr1 53BP1 through multiprotein complex. It is known that 53BP1 involved in restoring DNA double strand breaks. Interaction between the two proteins leads to the fact that 53BP1 directed to protein degradation, thus reducing its ability to repair DNA. Importantly, the researchers have shown that mice lacking βarr1, survived longer after treatment AI than normal control mice. This demonstrates that the expression of loss βarr1 associated with resistance to the toxic effects of radiation therapy.

"These studies suggest that pharmacological blockade of the signaling cascade βarr1-53BP1 provides a new strategy for the development of therapeutic agents with properties of radiation protection through improved repair of double-stranded DNA breaks caused by the AI" - explained Duquette.

Currently in development are several drugs that can provide protection against the AI; However, these agents are aimed at factors other than themselves DNA breaks. "We expect that simulates phenotype pharmacologically βarr1 will be an effective measure to counter the AI, and also can improve the efficiency of the molecules under study", - said McDonald.

Source: https://www.sciencedaily.com/releases/2019/10/191002112629.htm

Date of publication: 
Thursday, October 3, 2019