Breakthrough cancer study upends assumptions

(TIMES OF ISRAEL) Israeli scientists have published research upending the long-held assumption that DNA mutations occur at random, a potentially major genetic breakthrough that could eventually lead to customised treatments for cancer and other diseases caused by genetic issues.

The peer-reviewed study by a Weizmann Institute of Science research team showed that when DNA strands are damaged, a repair enzyme’s ability to fix the site depends heavily on the DNA’s physical shape and structure, which can either attract repair enzymes or physically block them from working.

“The local physical environment around DNA damage can strongly affect how it is repaired,” Weizmann’s Dr Ariel Afek, who supervised the research, told The Times of Israel. “If it bends in one direction or twists in another, it could make the efficiency of the repair a hundred times easier or harder.”

Noga Levy led the research at Afek’s lab at Weizmann along with other Weizmann researchers and Professor Brian P. Weiser and other scientists at Rowan University in New Jersey.

The scientists’ findings, which appeared in July in Nature Communications, relied on specialised DNA microchips developed by the team to test thousands of genetic strands simultaneously.

The researchers combined their experimental results with computer simulations that modelled atomic interactions, using genomic algorithms to cross-reference their findings with human cancer databases.

“Some researchers look at the mutation in cancer patients,” Afek said. “But we wanted to go back and look at the process that actually initiated the mutation at an atomic level a long time ago to really understand the mechanism and the molecular causes.”

According to Afek, these insights could eventually enable scientists to customise repair enzymes and to develop targeted therapies for diseases linked to genetic damage, including cancer and neurodegenerative disorders.

“Why do damaging agents like UV light from the sun, or oxidation from the air, hit specific places in the genome more than others, and why do repair enzymes fail to fix the damage in certain spots?” Afek asked. “Mutations stand at the essence of many genetic diseases, and we are trying to understand the building blocks that make mutations happen or not.”

What Afek and his colleagues set out to figure out was why some breaks get patched up but others don’t, and whether what is happening near the damaged area has anything to do with the answer.

“People have usually thought that if there’s damage, it doesn’t really matter what surrounds it, and that the nearest neighbour might have a small effect,” he said.

Afek’s team set out to isolate the initial steps to understand the process.

“Usually in the cell, if there is some damaging agent, maybe one place in the genome gets damaged and not another,” he said. “It’s very hard to control, but under lab conditions, we made millions of different DNA sequences, placing the damage in the same location.”

This allowed the scientists to follow the activity of the repair enzymes based on the surrounding sequences.

“For the first time, we could characterise all the preferences of the repair enzymes, and we started to understand what governs the binding and repair efficiency, and what leads to mutations.”