Microscopic Paramedics and Emergency Room for DNA Rescue and Repair

Repeated DNA sequences have had the bad nickname “junk DNA” for about 20 years. Scientists decoding the genome called it junk because they were initially focused on understanding the functions of individual genes.

Since then, studies have shown that repeated DNA sequences are in fact essential for many nuclear activities, but their defective repair is also linked to aging and disease.

“Heterochromatin is mostly composed of repeated DNA sequences,” Chiolo said. “The low gene content is part of the reason why these sequences are less characterized.”

In fact, mutations that compromise heterochromatin repair result in massive chromosome rearrangements affecting the entire genome.

The scientists found that after the DNA strands are broken, the cell prompts a series of threads — nuclear actin filaments — to assemble and create a temporary highway to the edge of the nucleus. Then come the paramedics — proteins known as myosins.

“Myosins are conveyed as a walking molecule because they have two legs. One is attached and the other moves,” Chiolo said. “It’s like a molecular machine that walks along the filaments.”

The myosins pick up the injured DNA, walk along the filament road and then reach the emergency room, a pore at the periphery of the nucleus.
In the ‘emergency room’

Based on a prior study, researchers knew that there was an “emergency room” — the nuclear pore where the cell fixes its broken DNA strands. Now, they have discovered how the damaged DNA travels there, Chiolo said.

“What we think is happening is that the damage triggers a defense mechanism that quickly builds the road, the actin filament, while also turning on an ambulance, the myosin.”

The researchers plan further studies examining the repair of DNA in heterochromatin.

“I’m excited to see how the molecular mechanisms we uncovered work in humans, as well as in plants that have much larger heterochromatin,” said Christopher Caridi, a co-lead author for the study and a postdoctoral researcher in Chiolo’s lab at USC Dornsife. It will be fascinating, he said, to see how such a complex repair mechanism functions and evolves over time and what aspects of the mechanisms may be adapted for other functions.

Contacts and sources:
Emily Gersema
University of Southern California

Citation: Nuclear F-actin and myosins drive relocalization of heterochromatic breaks.
Christopher P. Caridi, Carla D’Agostino, Taehyun Ryu, Grzegorz Zapotoczny, Laetitia Delabaere, Xiao Li, Varandt Y. Khodaverdian, Nuno Amaral, Emily Lin, Alesandra R. Rau, Irene Chiolo. Nature, 2018; DOI: 10.1038/s41586-018-0242-8