Chinese researchers have determined the near-atomic structure of a protein crucial for repairing damaged DNA, an advance that may shed light on novel effective cancer therapies.
Cells in our body continuously replicate to repair and replace damaged tissue, and each division requires a reprinting of the cell’s DNA.
As the DNA duplicates, errors inevitably occur, resulting in damage that, if left unrepaired, can lead to cellular death.
At the first hint of DNA damage, a protein known as an ATR kinase activates the cell’s built-in repair system.
A team led by Professor Gang Cai of the University of Science and Technology of China now imaged this protein at a resolution an order of magnitude higher than previous measurements, according to the study published in the Friday issue of the journal Science.
“The ATR protein is the apical kinase to cope with the DNA damages and replication stress,” said Cai.
“It has long been a central question to determine the activation mechanism of ATR kinase — how it responds to DNA damage and how it is activated,” he said.
Cai and his team used cryo-electron microscopy to image the so-called Mec1-Ddc2 complex at 3.9 angstroms, which is about eight times the size of a single atom of helium.
The complex is found in yeast and is the equivalent of the human ATR protein and its cell-signaling protein partner, ATRIP.
This led to the production of a crystal clear, three-dimensional structure at near-atomic resolution.
Previously, the ATR kinase structure has a resolution of about 22.5 angstroms.
The high-resolution structural information revealed regulatory sites of the ATR kinase, which are poised to activate at the first hint of DNA damage.
ATR has long been a potential therapeutic target, and elucidating its regulatory mechanism could aid in the development of new therapeutics, said Cai.
Preclinical evidence showed that ATR inhibitors substantially enhance the efficacy of both chemotherapy and radiotherapy, and several agents have recently entered clinical trials, he said.
“The development of more specific and efficient ATR inhibitors holds the promise for significant cancer treatment improvement,” he said.
“Therefore, the work provides a molecular blueprint for the development of novel ATR inhibitors as potential cancer therapeutic agents.”