DNA repair aided by protein gluing broken ends together

A protein involved in DNA damage repair, PARP1, has been likened to superglue due to its crucial role in holding together the broken DNA ends.

Double-stranded breaks are the most harmful form of DNA damage. They create two loose ends that, if left unrepaired, may lead to cell death. PARP1 has long been recognised as a DNA damage detector – it scours the DNA molecules to identify breaks and promote repair. However, until now, the mechanism preventing broken DNA ends from separating during the repair process has remained unclear. Scientists from Dresden University of Technology, Germany, have uncovered PARP1's key mechanism: the sticky protein holds the ends of the DNA together while cordoning off the injury site in the cell to allow for full repair of the DNA.

'We call this glue a condensate, which is a cluster of tightly interconnected protein and DNA molecules that are isolated from the rest of the cell. This glue forms a special healing zone. It not only keeps the DNA ends together but also lets DNA repair proteins do their job,' said Simon Alberti, professor of cellular biochemistry at BIOTEC Dresden University of Technology, Germany and senior author of the paper published in Cell.

After gluing together the DNA ends, PARP1 switches gears and recruits further repair proteins, including one called FUS. In this study, the scientists demonstrated that FUS is also key in regulating the repair process. FUS acts as a lubricant to 'soften the glue' and provide access for the repair proteins to complete their jobs in the crowded healing area.

The researchers used cutting-edge techniques to reconstitute the double-strand breaks in a test tube, providing them with a clearer view of the mechanistic steps involved in repair. To their knowledge, this marks the first time a double-strand break repair has been recreated outside of a cell.

PARP1 is the target of a class of cancer drugs, such as the approved chemotherapy drug rucaparib (see BioNews 1094). This new understanding of PARP1, and FUS, provides important insights into how these treatments may work in selectively killing cancer cells.

'Our data suggests a model in which the cancer treatment would impair the PARP1 superglue so that it remains stuck on DNA. In this way, it would generate roadblocks for the replication machinery of cancer cells, triggering them to commit suicide. We need more research to confirm the mechanism in more detail,' concluded Professor Alberti.