Researchers from the Medical Laboratory and Molecular Biology Laboratory at Imperial College London have collaborated to unravel a decades old mystery. They revealed the fundamental mechanisms for identifying DNA damage and initiating its repair. This study uses cutting-edge imaging techniques to visualize how DNA repair proteins move on individual DNA molecules and uses electron microscopy to capture how they 'lock onto' specific DNA structures, opening up new avenues for more effective cancer treatment. The relevant paper was published in the latest issue of the journal Nature. This study focuses on a DNA repair pathway known as the Fanconi anemia (FA) pathway. In fact, DNA is constantly damaged by environmental factors, including ultraviolet radiation, alcohol consumption, smoking, pollution, and so on. Crosslinking is a way in which DNA is damaged, which prevents normal DNA replication and gene expression. The accumulation of DNA damage may lead to cancer. In order to self replicate and read and express genes, the two strands of the DNA double helix structure must first be unfolded into a single strand, forming a Y-shaped replication fork. When DNA undergoes cross-linking, the "nucleosides" of the two strands stick together, preventing this unraveling. The research team has previously discovered that the protein complex D2-I composed of FANCD2 and FANCI proteins plays a role in the first step of the FA pathway. It clamps DNA, thereby initiating DNA repair during cross-linking. However, the key issue is how D2-I recognizes cross-linked DNA and why D2-I complexes are also associated with other types of DNA damage? The team used microscopy technology to identify a specific part of FANCD2 protein - the KR helix. Single molecule imaging experiments have shown that KR helices are crucial for identifying and stagnating in single stranded DNA gaps. Further research suggests that the D2-I complex's ability to utilize KR helices to arrest at these junctions is crucial for DNA repair in the FA pathway. Research has shown that it is the DNA structure within the replication fork, rather than the DNA cross-linking process itself, that triggers the D2-I complex to stop sliding and clamp DNA to initiate repair. These stagnant replication forks appear in many types of DNA damage, which explains the broad role of D2-I complexes in other forms of DNA repair and through the FA pathway. Understanding the process of DNA repair and the reasons for its failure is of great significance. Many anti-cancer drugs work by causing severe damage to cancer cells, causing them to stop dividing and die. In this case, the DNA repair pathway may be utilized by cancer cells to develop drug resistance. Understanding the mechanism of the first step in DNA repair pathway may help find ways to improve cancer cell drug sensitivity. (New Society)