Key points:
- Researchers discovered that the protein PARP1 acts an underwater superglue that holds loose DNA ends together during the damage repair process.
- After gluing DNA, PARP1 becomes active as an enzyme that recruits downstream DNA damage proteins that work in concert to detect and reverse damage.
- PARP1 is already a target of approved cancer treatments as inhibiting its activity selectively kills cancer cells, but this study provides new insight into the molecular basis of these therapies.
Researchers have discovered that the protein poly(ADP-ribose) polymerase 1 (PARP1) acts an underwater superglue that holds loose DNA ends together. Their results, published in Cell, describe the key role of PARP1 in double-strand DNA damage repair.
Researchers used high-end biochemical and biophysical methods including single-molecule imaging, optical tweezers, and quantitative biochemistry to identify PARP1 DNA repair mechanisms. However, the key experimental step was recreating the DNA damage site from the bottom-up in a test tube, which allowed the team to identify mechanistic insights into the regulation of DNA repair.
With this method, the researchers determined that PARP1 forms a drop of underwater superglue called a condensate that prevents the separation of the damaged DNA ends. The tight cluster of interconnected protein and DNA molecules form a special healing zone that allows DNA repair proteins to do their job.
After gluing DNA, PARP1 becomes active as an enzyme that recruits downstream DNA damage proteins such as Fused in Sarcoma (FUS). In this study, researchers demonstrated that FUS acts as a lubricant and softens the glue for repair enzymes to work.
“It’s an example of collective protein behavior that results in higher-order functionality,” said senior scientist Titus Franzmann of Technische Universität Dresden. “Every protein does its own job, but they all must collaborate to accomplish the goal of detecting and reversing the DNA damage.”
PARP1 is already a target of approved cancer treatments as inhibiting its activity selectively kills cancer cells, but now this study provides new insight into the molecular basis of these therapies.
“Our data suggests a model in which the cancer treatment would impair the PARP1 superglue so that is remains stuck on DNA,” explained senior author Simon Alberti, professor at Technische Universität Dresden. “In this way, it would generate roadblocks for the replication machinery of cancer cells, triggering them to commit suicide.”