Scientists from the University of Toronto have found a DNA repair mechanism that enhances our knowledge of how human cells maintain their health, and could potentially result in new therapies for cancer and premature aging.
The research, which was published in the journal Nature Structural and Molecular Biology, also provides insight into how certain chemotherapy drugs work.
“We believe this discovery has the potential to revolutionize the way we approach cancer treatment and aging-related diseases,” said one of the researchers involved in the study.Professor Karim Mekhail, co-principal investigator on the study and a professor of laboratory medicine and pathobiology at U of T’s Temerty Faculty of Medicine, stated that the research has uncovered the connection between DNA double-strand breaks and the nuclear envelope for repair in human cells. He also emphasized that this discovery will accelerate scientific progress by applying previous findings in other organisms to the context of human DNA repair. DNA double-strand breaks are a result of exposure to radiation and chemicals, as well as internal processes like DNA replication, making them a highly significant form of DNA damage.
Damage can hinder or accelerate cell growth, which can lead to aging and cancer.
The recent breakthrough, achieved in collaboration with Professor Razqallah Hakem, a researcher at University Health Network and professor at Temerty Medicine, builds on previous research on DNA damage in yeast by Mekhail and others. In 2015, Mekhail and colleagues demonstrated how motor proteins inside the nucleus of yeast cells transport double-strand breaks to protein complexes located in the nuclear envelope at the perimeter of the nucleus, resembling a ‘DNA hospital’.
Other studies have also revealed the significance of DNA damage in cell function.
Researchers have found that DNA repair mechanisms in flies and other organisms are different from those in human and mammalian cells. Scientists were puzzled by the limited movement of damaged DNA in mammalian cells despite the importance of nuclear envelope proteins in DNA repair. They discovered that when DNA is damaged in a human cell’s nucleus, a network of microtubule filaments forms in the cytoplasm and pushes against the nuclear envelope.
The creation of tiny tubes, or tubules, that extend into the nucleus and capture most double-strand breaks is triggered by this process. According to Mekhail, it’s comparable to pressing on a balloon. The pressure from your fingers forms tunnels in its structure, causing some parts of the balloon’s exterior to fold inside itself. The researchers’ further investigation detailed various aspects of this mechanism. The master regulators of the process are enzymes known as DNA damage response kinases and tubulin acetyltransferase, which promote the formation of the tubules. Enzymes also leave a chemical mark on a  specific part of the microtubule filaments recruits small motor proteins and pushes on the nuclear envelope, leading to the repair-promoting protein complexes pushing the envelope deep into the nucleus. This creates bridges to the DNA breaks.
“This ensures that the nucleus undergoes a form of reversible metamorphosis, allowing the envelope to temporarily infiltrate DNA throughout the nucleus, capturing and reconnecting broken DNA,” says Mekhail.
These findings have significant implications for some cancer treatments.
Normal cells utilize the nuclear envelope tubules to repair DNA, but cancer cells seem to rely on them.The team examined data from over 8,500 cancer patients to understand the potential impact of the mechanism. The need for new treatment options was evident in various cancers, including triple-negative breast cancer, known for its aggressiveness.
“Finding new therapeutic approaches for cancer patients is a major focus, and this discovery is a significant advancement,” says Hakem, a senior scientist at UHN’s Princess Margaret Cancer Centre and a professor in U of T’s department of medical biophysics and department of laboratory medicine and pathobiology.
<p”Previously, scientists were unsure about the nuclear envelope’s relative impact.The study focused on the role of nuclear envelope in repairing damaged DNA in human cells. The researchers found that targeting factors that influence the nuclear envelope’s function in DNA repair can effectively slow down the development of breast cancer, especially the aggressive triple negative type. This type of breast cancer has higher levels of tubules, likely due to increased DNA damage. By manipulating the genes controlling these tubules, the researchers were able to reduce the ability of cancer cells to form tumors. In the treatment of triple negative breast cancer, PARP inhibitors, a type of medication, are commonly used. PARP is an enzyme that assists in DNA repair.air damaged DNA. PARP inhibitors prevent the enzyme from repairing, which stops the DNA double-strand break in cancer cells from reconnecting.
This causes the cancer cells to join two broken ends that are not meant to be joined, resulting in DNA structures that are unable to be copied and divided.
“Our research demonstrates that the drug’s ability to create these mismatches depends on the tubules. When there are fewer tubules, cancer cells become more resistant to PARP inhibitors,” Hakem explains.
Collaboration among researchers in different fields was crucial forThe study highlights the significance of collaborating across different disciplines in order to better understand cancer cells, according to Mekhail. He emphasizes the importance of having a strong team and how each member contributes to the research. Mekhail also mentions that the findings have implications for conditions such as progeria, a rare genetic disorder that causes premature aging and is associated with mutations in the gene coding for lamin A. These mutations decrease the stability of the cell nucleus, leading to accelerated aging and early mortality.The researchers discovered that the nuclear envelope becomes unstable as a result of mutant lamin A expression. This instability leads to the formation of tubules, which are further increased by DNA damaging agents. The team believes that even slight pressure on the nuclear envelope can cause the premature aging cells to form tubules.
This study indicates that in progeria, the presence of too many or poorly regulated tubules may compromise DNA repair. The implications of these findings extend to numerous other clinical conditions, according to Mekhail.
Mekhail is excited about the potential implications of these findings. He looks forward to where this research will lead, acknowledging the support of his colleagues and trainees.At Temerty Medicine and our partner hospitals, we are actively pursuing the implementation of this discovery into the development of new therapeutics.
