DNA Repair Skips Heavy Lifting, Goes with the Flow

A cryogenic electron microscopy map of UV-DDB, a DNA repair protein complex, is shown on the right, beside the nucleosome to the left. The UV-DDB may bind to DNA lesions in the nucleosome, whether they are directly accessible or “occluded,” without the assistance of chromatin remodeling proteins. [FMI]

DNA repair proteins are like home repair contractors. Both need to access sites of damage. Whereas a DNA repair protein needs to navigate tightly packed chromatin, a contractor must get around, or through, a client’s belongings, whether the client is a hoarder or a feng shui enthusiast. Luckily for DNA repair proteins, chromatin has far more feng shui than a casual glance might suggest.

DNA repair proteins may detect and bind to damaged DNA—even if it seems to be buried within nucleosomes—by means of a newly discovered mechanism. This mechanism allows the DNA repair protein to take advantage of the intrinsic dynamics of nucleosomal DNA, to “go with the flow.” There is no need for additional molecular personnel, such as nucleosome-shifting proteins. No heavy lifting—that is, no chromatin remodeling—is required.

The new mechanism was discerned by researchers from the Friedrich Miescher Institute for Biomedical Research (FMI). Using cryogenic electron microscopy, they observed a molecular contractor called UV-damaged DNA-binding protein (UV-DDB). They were particularly interested in observing how UV-DDB manages to bind to a DNA lesion when the DNA in the lesion’s vicinity is coiled around the nucleosome’s histone core.

UV-DDB appears to catch UV lesions when they are temporarily available. In other words, UV-DDB is opportunistic, deftly exploiting large openings or diligently making elbow room for itself whenever small openings appear. Details about UV-DDB’s work habits appeared May 29 in Nature, in an article titled, “DNA damage detection in nucleosomes involves DNA register shifting.”

“We find that UV-DDB binds UV-damaged nucleosomes at lesions located in the solvent-facing minor groove without affecting the overall nucleosome architecture,” the article’s authors wrote. “In the case of buried lesions that face the histone core, UV-DDB changes the predominant translational register of the nucleosome and selectively binds the lesion in an accessible, exposed position.”

After determining various three-dimensional structures of UV-DDB bound to lesions at different locations around the nucleosome, the researchers concluded that damage detection strategies depend on where the DNA lesion is located. In the case of “accessible” lesions, which can be directly contacted, UV-DDB binds to the lesion tightly. The recognition of “occluded” lesions (facing the histone protein core of the nucleosome) requires additional steps: UV-DDB binds the UV lesions when they are exposed temporarily through the natural dynamics of the nucleosome.

“To visualize what happens at the molecular level, imagine a piece of string wrapped around a spool, which becomes accessible when it is pulled forwards or backwards a little bit,” said Syota Matsumoto, an FMI researcher and the lead author of the Nature paper.

The researchers called the mechanism of DNA damage read-out “slide-assisted site-exposure.” This new mechanism operates independently of chromatin remodelers and does not require chemical energy to slide or dislodge nucleosomes.

“In the past, nucleosomes were thought to be a major obstacle for DNA-binding proteins,” commented Nicolas H. Thomä, the paper’s corresponding author and the head of an FMI lab. “In our study, we show that they are not, and that the system is tailored to bind UV lesions wherever they are.

“What makes this study really powerful is the fact that the mechanism we identified could very well be used by many other types of DNA-binding proteins. Accessing nucleosomal DNA is not only fundamental for DNA repair, but also is relevant for all proteins that bind to chromatin. With our study, we define a previously unknown strategy for protein access to chromatinized DNA templates.”

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