Novel discovery could lead to targeted cancer therapies.
Findings from a study published by Science suggest that there may be a way to salvage healthy cells from detrimental DNA damage sustained during cancer treatment. The authors suggest that an experimental treatment could repair DNA-protein crosslink (DPC).
The investigators discovered that the ZATT protein reverses DPCs with assistance from the TDP2 protein. Since DPCs occur after certain cancer therapies, understating the link between TDP2 and ZATT is crucial for improving health outcomes of patients with cancer, according to the authors.
Previously, it was known that TDP2 was involved with removing DPCs, but it was unknown how it was directed to where it was needed.
In the new study, the authors used a multi-faceted approach to reveal ZATT’s role in the process and discover how the protein helps TDP2 find and repair DPCs.
The authors started by identifying how DPCs are created to determine how the proteins initiate a repair. They said that when DNA becomes tangled, the topoisomerase 2 (TOP2) is used to untangle it, according to the study.
"Imagine your DNA is a giant ball of yarn," said lead author Matthew Schellenberg, PhD. "TOP2 cuts and reties individual threads to disentangle the ball."
Typically, TOP2 hides its cut DNA ends within the core of the protein’s core that houses the DNA, which allows TOP2 to rejoin DNA ends, according to the study.
Chemotherapy and environmental chemicals can prevent DNA from retying itself, causing TOP2 to remain stuck on the DNA. The authors report that this occurrence creates a stable TOP2-DPC complex and leads to the aggregation of severed DNA that can kill cells.
TOP2-DPCs are “ticking time bombs,” according to corresponding author Scott Williams, PhD. The molecular changes are heightened by TOP2 interactions with toxins, chemical metabolites, and tobacco or UV light exposure.
Additionally, potent TOP2-DPCs are created by cancer drugs. While TOP2-DPCs can treat cancer, they can also be a cause of the disease since they can rearrange the genome, according to the study.
In order to target DPCs, the authors explored how the damage is located and reversed.
"In this study, we discovered a new molecular disarmament apparatus for these cell-killing bombs," Dr Williams said. "ZATT is like a bomb sniffing dog, so when it locates its target, it sounds an alarm to mobilize the recruitment of TDP2, which cuts the red wire to disarm these threats."
In addition to chemotherapies, many antibiotics induce DPCs to damage bacterial DNA.
These findings are a part of a larger effort to discover how to exploit this vulnerability to improve patient outcomes and develop more targeted therapies, according to the study.
"We’ve discovered how we defend against this potent means of cell killing," Dr Schellenberg said. "It is our hope that this information will enable development of new drugs that target these defenses. By lowering the defenses, we may make drugs that kill cancer cells more effective."