Glue enzyme helps with DNA repair

Glue enzyme helps with DNA repair

A special protein acts as a glue for the DANN and thus enables gene repair. © Magdalena Gonciarz, generated with Dall-E3

When our DNA is damaged, numerous repair enzymes ensure that the damage is quickly repaired. A study now shows what processes occur when both strands of DNA are broken. To prevent the loose ends from drifting apart, an enzyme called PARP1 has an effect similar to that of superglue: As soon as the damage is discovered, the enzymes combine with each other and with the DNA ends, thus creating the basis for repair. The findings improve the understanding of DNA repair and may also be relevant for cancer research.

Numerous internal and external influences ensure that the DNA in our cells repeatedly suffers damage. UV radiation, chemicals and also normal metabolic processes can cause individual parts of the genetic material to be copied incorrectly or one or both DNA strands to break. In order to quickly repair such damage, numerous repair enzymes patrol the DNA, providing first aid if necessary and sounding the alarm to activate further repair enzymes. However, the exact processes involved have so far only been partially understood. One of the puzzles was how the cell manages to ensure that when double-strand breaks occur, the loose DNA ends do not move too far apart, which would make repairs more difficult.

Glue and alarm device at the same time

A team led by Nagaraja Chappidi from the Technical University of Dresden has now gotten to the bottom of this question. “How cells prevent the separation of broken DNA ends has been a mystery until now. We have now found that this is mediated by a protein called PARP1, which has long been known as a sensor for DNA damage,” says Chappidi’s colleague Simon Alberti. It was already known that in the event of DNA damage, the PARP1 protein can activate other repair enzymes that repair a broken DNA strand.

As the new results now show, when double-strand breaks occur, PARP1 acts like a glue that connects the two loose ends together. “We call this glue a condensate, which is a collection of densely connected protein and DNA molecules that are isolated from the rest of the cell and form a special repair chamber. This glue not only holds the DNA ends together, but also allows DNA repair enzymes to do their work,” explains Alberti.

Collective collaboration

In order to understand the processes in detail, the researchers reconstructed the DNA damage scenario outside the cells in the test tube. They used purified proteins and DNA in which they created double-strand breaks. “This allowed us to determine the exact molecular events that underlie the formation of DNA damage repair sites,” says Chappidi. “But PARP1 condensation is just the beginning. After it clumps with the DNA, PARP1 becomes active as an enzyme and recruits a series of downstream DNA repair proteins.” These include a protein called FUS. This acts like a lubricant that softens the condensate so that further repair enzymes can do their work.

“This is an example of collective protein behavior leading to higher functionality. Each protein does its own job, but all proteins must work together to achieve the goal of detecting and repairing DNA damage,” says Chappidi colleague Titus Franzmann. The study thus uncovers the molecular mechanisms of how broken DNA ends remain spatially connected while allowing access for repair factors. Chappidi and his colleagues believe that the method of replicating DNA repair outside of cells in the test tube could also be relevant for other research teams. “We believe it will be a great asset to the scientific community that studies DNA damage,” says Chappidi.

Target for cancer therapies

The new findings could also be relevant for cancer research. “Because of its role in DNA repair, PARP1 is already the target of many approved cancer therapies,” explains Alberti. PARP1 is specifically inhibited, while at the same time other chemotherapy drugs damage the DNA of the cancer cells. Without the PARP1 protein, this damage can no longer be adequately repaired, so the cancer cells ideally die. “Our work reveals the molecular and physical basis for why these cancer therapies are so successful,” says Alberti.

Source: Nagaraja Chappidi (TU Dresden) et al., Cell, doi: 10.1016/j.cell.2024.01.015

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