Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:


Damaged DNA May Stall Patrolling Molecule to Initiate Repair


Sites where DNA is damaged may cause a molecule that slides along the DNA strand to scan for damage to slow on its patrol, delaying it long enough to recognize and initiate repair. The finding suggests that the delay itself may be the key that allows the protein molecule to find its target, according to researchers at the University of Illinois at Chicago.

Usually, the repair protein zips along quickly, says Anjum Ansari, UIC professor of physics and co-principal investigator on the study, published this month in Nature Communications.

Illustration: Myrna Romero and Jung-Hyun Min.

XPC DNA repair protein shown in two modes, patrolling undamaged DNA (in green) and bound to DNA damage site (magenta, with blue XPC insert opening the site). The sun behind the molecule is a reminder that the sun is the primary source of lesions recognized by XPC.

“If the DNA is normal and the protein is searching, the interaction that the protein makes with the DNA is not very tight, and the protein is able to wander at some speed,” Ansari said.

“When the protein encounters a damaged DNA, it’s not quite like a normal DNA , it may be a little twisted or more flexible. The protein ‘stumbles’ at that spot and gets a little stalled, enough to give it a little bit more time at the damaged site,” she said. “The longer it sits, the higher the probability that it will open the DNA and initiate repair.”

This ‘stumble’ gives the protein time to flip out the damaged nucleotide building blocks of the DNA and recruit other proteins that begin repair, said Jung-Hyun Min, assistant professor of chemistry at UIC and co-principal investigator on the study.

The protein, xeroderma pigmentosum C or XPC, is important for the repair of DNA damaged by environmental insults, like the chemicals in cigarette smoke and pollutants, which makes it important for preventing cancers, Min said. Dysfunctional XPC may lead to a 1,000-fold increase in the risk of skin cancer.

How the protein can find a lesion hidden among perhaps 100,000 times as many undamaged nucleotides has been a mystery, Min said. XPC is unusual in that it does not have a “pocket” that fits one specific damaged structure while rejecting others that do not fit well. Instead, it recognizes damage indirectly, and so is able to repair a variety of derangements.

In order to see how XPC distinguishes between normal and damaged DNA, the researchers used a chemical trick to bind the protein to a single site on intact DNA. To their surprise, they found that the protein flipped open the nucleotides on undamaged DNA just as it does at a bad spot.

The finding suggested that, if held in one place long enough, XPC could open even undamaged DNA. Using a technique called temperature-jump perturbation spectroscopy to observe the interaction of XPC with DNA in real time, the researchers determined that the protein needed several milliseconds to flip open DNA at a damaged site.

“We think it could take as much 4,000 times as long to open DNA at an undamaged versus damaged site,” said Ansari. The XPC protein moves too quickly to engage undamaged DNA, but is stalled by a twisted damage site long enough to flip out the bad nucleotides and initiate repair.

This dependence on how quickly the protein could open up the DNA before moving on suggests an entirely new kind of binding-site recognition, said Min.

“This has a potential to explain the kind of phenomena that we couldn’t explain before," Min said, such as how the protein turns up in some places where the DNA does not harbor damage that XPC would be expected to recognize on its own.

"This may be done, for example, through interactions with other proteins that can bring XPC there and stall it for a moment," she said. "It may be that all you need is to bring the protein to these sites and stall it for a moment.”

The researchers believe that this "delay-triggered kinetic gating" could be a common mechanism among many other types of DNA recognition proteins.

Xuejing Chen, UIC chemistry, and Yogambigai Velmurugu, UIC physics, are co-first authors on the study. Beomseok Park, Yoonjung Shim of UIC chemistry; Guanqun Zheng, and Chuan He of University of Chicago; Younchang Kim of Argonne National Laboratory and Lili Liu and Bennett Van Houten of the University of Pittsburgh are co-authors.

This study was funded by the UIC’s Chancellor’s Discovery Fund; Chicago Biomedical Consortium’s Catalyst Award with support from the Searle Funds at The Chicago Community Trust; National Institutes of Health grants GM0771440 and 1RO1ES019566; National Science Foundation Grants MCB-0721937 and MCB-115821; and a UIC startup fund.

Contact Information
Jeanne Galatzer-Levy
Associate Director, News Bureau
Phone: 312-996-1583

Jeanne Galatzer-Levy | newswise
Further information:

More articles from Life Sciences:

nachricht Molecular doorstop could be key to new tuberculosis drugs
20.03.2018 | Rockefeller University

nachricht Modified biomaterials self-assemble on temperature cues
20.03.2018 | Duke University

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Mars' oceans formed early, possibly aided by massive volcanic eruptions

Oceans formed before Tharsis and evolved together, shaping climate history of Mars

A new scenario seeking to explain how Mars' putative oceans came and went over the last 4 billion years implies that the oceans formed several hundred million...

Im Focus: Tiny implants for cells are functional in vivo

For the first time, an interdisciplinary team from the University of Basel has succeeded in integrating artificial organelles into the cells of live zebrafish embryos. This innovative approach using artificial organelles as cellular implants offers new potential in treating a range of diseases, as the authors report in an article published in Nature Communications.

In the cells of higher organisms, organelles such as the nucleus or mitochondria perform a range of complex functions necessary for life. In the networks of...

Im Focus: Locomotion control with photopigments

Researchers from Göttingen University discover additional function of opsins

Animal photoreceptors capture light with photopigments. Researchers from the University of Göttingen have now discovered that these photopigments fulfill an...

Im Focus: Surveying the Arctic: Tracking down carbon particles

Researchers embark on aerial campaign over Northeast Greenland

On 15 March, the AWI research aeroplane Polar 5 will depart for Greenland. Concentrating on the furthest northeast region of the island, an international team...

Im Focus: Unique Insights into the Antarctic Ice Shelf System

Data collected on ocean-ice interactions in the little-researched regions of the far south

The world’s second-largest ice shelf was the destination for a Polarstern expedition that ended in Punta Arenas, Chile on 14th March 2018. Oceanographers from...

All Focus news of the innovation-report >>>



Industry & Economy
Event News

Virtual reality conference comes to Reutlingen

19.03.2018 | Event News

Ultrafast Wireless and Chip Design at the DATE Conference in Dresden

16.03.2018 | Event News

International Tinnitus Conference of the Tinnitus Research Initiative in Regensburg

13.03.2018 | Event News

Latest News

Physicists made crystal lattice from polaritons

20.03.2018 | Physics and Astronomy

Mars' oceans formed early, possibly aided by massive volcanic eruptions

20.03.2018 | Physics and Astronomy

Thawing permafrost produces more methane than expected

20.03.2018 | Earth Sciences

Science & Research
Overview of more VideoLinks >>>