Molecular sensor scouts for DNA damage

Scientists at the University of Pittsburgh have revealed how a particular protein keeps DNA damage in check, preventing cancer from running rampant throughout our bodies. Their work has been published in the journal Nature Structural and Molecular Biology.

The scientists claim that a protein called UV-DDB — which stands for ultraviolet-damaged DNA-binding — is useful beyond safeguarding against the Sun, as its name suggests. Rather, their research points to UV-DDB being a scout for general DNA damage and an overseer of the molecular repair crew that fixes it.

“If you’re going to fix a pothole, you have to find it first,” said Professor Bennett Van Houten, senior author on the study. “That’s what UV-DDB does. It identifies DNA damage so that another crew can come in and patch and seal it.”

Prof Van Houten acknowledged that surveying 3 billion base pairs, packed into a nucleus just a few microns wide, is a tall order; not only is it a lot of material to search through, but it’s wound up so tightly that many molecules can’t access it. So how does UV-DDB manage it?

Keeping with the pothole analogy, one possible search strategy is to walk along the road, waiting to step in a hole. Another option is to fly around in a helicopter — but since molecules can’t ‘see’, this approach would require frequently landing to look for rough patches. To get around these shortcomings, UV-DDB combines both search strategies.

“UV-DDB is like a helicopter that can land and then roll for a couple blocks,” Prof Van Houten said. “It also has the ability to find damage buried in chromosomes and help DNA repair molecules go places they otherwise couldn’t, the way a helicopter can navigate really hilly areas.”

When UV-DDB finds damage, it acts like a foreman to help the DNA repair crew get in, fix the faulty bases and detach quickly. Prof Van Houten’s team witnessed this process along a ‘tightrope’ of DNA slung between two silica beads, using real-time, single-molecule imaging.

“The amazing thing is finding those single molecules in 3D space,” said study co-author Simon Watkins. “[Van Houten]’s team has developed an assay that allows them to track the repair enzymes in 3D on the DNA ropes as they repair damage.”

To show that UV-DDB performs the same functions in living cells, Prof Van Houten and his team inflicted oxidative damage to the chromosomes’ protective endcaps, called telomeres. As in the DNA tightrope experiment, UV-DDB rushed to the scene — and when it wasn’t available, cells were more sensitive to oxidative stress.

These results help to explain why children born without functional UV-DDB — a rare disease known as xeroderma pigmentosum — are virtually guaranteed to develop skin cancer from sun exposure, Prof Van Houten said. On the other end of the spectrum, cancer patients with higher levels of UV-DDB respond better to therapy.

“It’s clear this protein is involved in a very fundamental problem,” he said. “We could not have evolved out of the slime if we didn’t have good DNA repair.”

Image caption: Single-molecule imaging of DNA repair. Image credit: Jang et al (2019) Nature Structural and Molecular Biology.

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