Scientists solve mystery of DNA damage detection and repair caused by sunlight, alcohol, and pollution

Good news! Amazing stuff! Cancer is history (soon)!

"A collaboration between researchers ... has solved a decades-old mystery which could pave the way to better cancer treatments in the future. ...
Using cutting edge imaging techniques to visualize how these DNA repair proteins move on a single molecule of DNA, and electron microscopy to capture how they "lock-on" to specific DNA structures, this research opens the way to more effective cancer treatments. ..."

"... The researchers were working on a DNA repair pathway, known as the Fanconi Anaemia [FA] pathway, which was identified more than twenty years ago. DNA is constantly damaged throughout our lives by environmental factors including UV light from the sun, alcohol use, smoking, pollution and exposure to chemicals. One way in which DNA becomes damaged is when it is “cross-linked”, which stops it being able to replicate and express genes normally. In order to replicate itself and to read and express genes, the two strands of the DNA double helix first has to unzip into single strands. When DNA is cross-linked, the “nucleotides” (the “steps” in the double-helix ladder of DNA) of the two strands become stuck together, preventing this unzipping.
The accumulation of DNA damages including cross-linking can lead to cancer. The FA pathway is active throughout our lives and identifies these damages and repairs them on an ongoing basis. Individuals who have mutations that make this pathway less effective are far more susceptible to cancers. Although the proteins involved in the FA pathway were discovered some time ago, a mystery remained over how they identified the cross-linked DNA and started the process of DNA repair.   ..."

From the abstract:

"DNA crosslinks block DNA replication and are repaired by the Fanconi anaemia pathway. The FANCD2–FANCI (D2–I) protein complex is central to this process as it initiates repair by coordinating DNA incisions around the lesion. However, D2–I is also known to have a more general role in DNA repair and in protecting stalled replication forks from unscheduled degradation. At present, it is unclear how DNA crosslinks are recognized and how D2–I functions in replication fork protection. Here, using single-molecule imaging, we show that D2–I is a sliding clamp that binds to and diffuses on double-stranded DNA. Notably, sliding D2–I stalls on encountering single-stranded–double-stranded (ss–ds) DNA junctions, structures that are generated when replication forks stall at DNA lesions. Using cryogenic electron microscopy, we determined structures of D2–I on DNA that show that stalled D2–I makes specific interactions with the ss–dsDNA junction that are distinct from those made by sliding D2–I. Thus, D2–I surveys dsDNA and, when it reaches an ssDNA gap, it specifically clamps onto ss–dsDNA junctions. Because ss–dsDNA junctions are found at stalled replication forks, D2–I can identify sites of DNA damage. Therefore, our data provide a unified molecular mechanism that reconciles the roles of D2–I in the recognition and protection of stalled replication forks in several DNA repair pathways."

Scientists solve mystery of DNA damage detection and repair caused by sunlight, alcohol, and pollution

FANCI that! Decades long mystery of how DNA damage by sunlight, alcohol and pollution is identified so it can be repaired, is solved. Opens up opportunities for improved cancer treatments. (original news release)

FANCD2–FANCI surveys DNA and recognizes double- to single-stranded junctions (open access)

DNA double helix, shown in yellow, embraced by the FANCID2-FANCI protein complex, which acts as a sliding clamp which surveys the DNA for damage and can “lock-on” to it to instigate repair when it detects a single-stranded gap in the DNA

Fig. 1: Single-molecule imaging of the D2–I clamp sliding on DNA.